Primary Resources in Immunology

Editorial board [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1

Fetal and early neonatal interleukin-6 response [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Claudio Chiesa, Lucia Pacifico, Fabio Natale, Nora Hofer, John F. Osborn, Bernhard Resch
In 1998, a systemic fetal cytokine response, defined as a plasma interleukin-6 (IL-6) value above 11 pg/mL, was reported to be a major independent risk factor for the subsequent development of neonatal morbid events even after adjustments for gestational age and other confounders. Since then, the body of literature investigating the use of blood concentrations of IL-6 as a hallmark of the fetal inflammatory response syndrome (FIRS), a diagnostic marker of early-onset neonatal sepsis (EONS) and a risk predictor of white matter injury (WMI), has grown rapidly. In this article, we critically review: IL-6 biological functions; current evidence on the association between IL-6, preterm birth, FIRS and EONS; IL-6 reference intervals and dynamics in the early neonatal period; IL-6 response during the immediate postnatal period and perinatal confounders; accuracy and completeness of IL-6 diagnostic studies for EONS (according to the Standards for Reporting of Diagnostic Accuracy statement); and recent breakthroughs in the association between fetal blood IL-6, EONS, and WMI.

Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Pushpa Pandiyan, Jinfang Zhu
CD4⁺CD25⁺Foxp3⁺ regulatory cells (T regs ) are a special lineage of cells central in the maintenance of immune homeostasis, and are targeted for human immunotherapy. They are conventionally associated with the production of classical anti-inflammatory cytokines such as IL-10, TGF-β and IL-35, consistent to their anti-inflammatory functions. However, emerging evidence show that they also express effector cytokines such as IFN-γ and IL-17A under inflammatory conditions. While some studies reveal that these pro-inflammatory cytokine producing Foxp3⁺ regulatory cells retain their suppressive ability, others believe that these cells are dys-regulated and are associated with perpetuation of immunopathology. Therefore the development of these cells may challenge the efficacy of human T reg therapy. Mechanistically, toll-like receptor (TLR) ligands and the pro-inflammatory cytokine milieu have been shown to play important roles in the induction of effector cytokines in T regs . Here we review the mechanisms of development and the possible functions of pro-inflammatory cytokine producing Foxp3+ T regs .

The interleukin (IL)-1 cytokine family – Balance between agonists and antagonists in inflammatory diseases [Cytokine– Balance between agonists and antagonists in inflammatory diseases]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Jennifer Palomo, Damien Dietrich, Praxedis Martin, Gaby Palmer, Cem Gabay
The interleukin (IL)-1 family of cytokines comprises 11 members, including 7 pro-inflammatory agonists (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) and 4 defined or putative antagonists (IL-1R antagonist (IL-1Ra), IL-36Ra, IL-37, and IL-38) exerting anti-inflammatory activities. Except for IL-1Ra, IL-1 cytokines do not possess a leader sequence and are secreted via an unconventional pathway. In addition, IL-1β and IL-18 are produced as biologically inert pro-peptides that require cleavage by caspase-1 in their N-terminal region to generate active proteins. N-terminal processing is also required for full activity of IL-36 cytokines. The IL-1 receptor (IL-1R) family comprises 10 members and includes cytokine-specific receptors, co-receptors and inhibitory receptors. The signaling IL-1Rs share a common structure with three extracellular immunoglobulin (Ig) domains and an intracellular Toll-like/IL-1R (TIR) domain. IL-1 cytokines bind to their specific receptor, which leads to the recruitment of a co-receptor and intracellular signaling. IL-1 cytokines induce potent inflammatory responses and their activity is tightly controlled at the level of production, protein processing and maturation, receptor binding and post-receptor signaling by naturally occurring inhibitors. Some of these inhibitors are IL-1 family antagonists, while others are IL-1R family members acting as membrane-bound or soluble decoy receptors. An imbalance between agonist and antagonist levels can lead to exaggerated inflammatory responses. Several genetic modifications or mutations associated with dysregulated IL-1 activity and autoinflammatory disorders were identified in mouse models and in patients. These findings paved the road to the successful use of IL-1 inhibitors in diseases that were previously considered as untreatable.

The catcher in the RIG-I [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Friedemann Weber
Retinoic-acid inducible gene I (RIG-I) is a major pattern recognition receptor of the innate immune system. RIG-I is a cytoplasmic RNA helicase that is able to bind virus-specific RNA structures. Activated RIG-I switches into a conformation that locks the ligand RNA and signals via the MAVS-IRF-3 axis, resulting in the upregulation of antiviral interferons. Recent evidence suggests that the binding of RIG-I to regulatory RNA structures of two major human pathogens, influenza A virus and hepatitis B virus, can inhibit viral replication independent of the subsequent signal transduction. Thus, RIG-I rides a two-pronged attack, with an early-hitting, direct inhibition via occupancy of viral regulatory RNA structures, and a delayed response via signaling and induction of interferons.

Beyond Candida albicans: Mechanisms of immunity to non-albicans Candida species [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Natasha Whibley, Sarah L. Gaffen
The fungal genus Candida encompasses numerous species that inhabit a variety of hosts, either as commensal microbes and/or pathogens. Candida species are a major cause of fungal infections, yet to date there are no vaccines against Candida or indeed any other fungal pathogen. Our knowledge of immunity to Candida mainly comes from studies on Candida albicans, the most frequent species associated with disease. However, non- albicans Candida (NAC) species also cause disease and their prevalence is increasing. Although research into immunity to NAC species is still at an early stage, it is becoming apparent that immunity to C. albicans differs in important ways from non- albicans species, with important implications for treatment, therapy and predicted demographic susceptibility. This review will discuss the current understanding of immunity to NAC species in the context of immunity to C. albicans , and highlight as-yet unanswered questions.

Making many from few: IL-12p40 as a model for the combinatorial assembly of heterodimeric cytokines [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Kaveh Abdi, Nevil J. Singh
How dendritic cells (DCs) gather information from the local milieu at a site of infection or injury and communicate this to influence adaptive immunity is not well understood. We and others have reported that soon after microbial encounter, DCs secrete the p40 subunit of IL-12, by itself, in a monomeric form. Based on recent data that this p40 monomer subsequently associates with p35 released from other cells to generate functional IL-12, we proposed that p40 can function as a DC-derived probe which samples the composition of the local milieu by looking for other binding partners. In this opinion, we discuss how such a sampling function might generate an elaborate combinatorial “code” of heterodimeric cytokines, capable of conveying location-specific information to cells downstream of DC activation, including NK and T cells.

ID: 5 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Yanick Crow
The dissection of the genetic basis of the rare inflammatory phenotype Aicardi-Goutières syndrome (AGS), and the ongoing definition of a primary link between nucleic acid metabolism and interferon signaling, led to the proposition, in 2011, of the grouping of Mendelian disorders associated with an up-regulation of type I interferon as a novel set of inborn errors of immunity, in which such up-regulation is central to pathogenesis. I will provide a brief update on these human type I interferonopathies, which I suggest can be usefully considered together at a clinical and pathological level, with the implication being that common treatment modalities might be applicable in the future.

ID: 6 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Raphaela Goldbach-Mansky
Autoinflammatory diseases are a group of rare immune dysregulatory syndromes that present with systemic inflammation manifesting with unexplained fevers, rashes, joint pain, and organ specific inflammation that often present very early in life. The discovery of the genetic causes of these diseases, revealed gain of function mutations in intracellular immune sensors or the generation of intracellular stress/danger signals that modify the regulation of innate immune sensing and lead to the activation of inflammatory mediators that from cytokine amplification loops. The elucidation of such pathways has provided new concepts to understand autoinflammatory diseases and allowed for the development therapeutic interventions that target disease specific pathways. While many of the early autoinflammatory diseases are mediated by activation of IL-1beta activating inflammasomes and can effectively be treated by IL-1 targeting therapies, a group of IL-1 therapy resistant autoinflammatory diseases are caused by dysregulation in viral sensor pathways and lead to chronic IFN stimulation. The dissection of immune dysregulation in two of these conditions including STING associated vasculopathy with onset in infancy (SAVI) and the proteasome associated autoinflammatory syndrome, CANDLE point to a causative role of Type I interferon dysregulation and instigated the initiation of IFN signaling blocking therapies. In other diseases immune receptor dysregulation may allow for targeting therapies that include the modification of other signaling molecules. Long-term outcome data provide evidence of continued benefit of such therapies.

ID: 255 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Takashi Fujita
MDA5 is an essential intracellular sensor for several viruses, including picornaviruses, and elicits antiviral interferon (IFN) responses by recognizing viral dsRNAs. Once MDA5 senses replicating viruses, it triggers signal to activate antiviral genes including those of types I and III IFN. Activation of IFN system is critical as antiviral innate immunity and promotes activation of acquired immunity. These immune responses orchestrate eradication of infecting viruses. On the other hand, MDA5 has been implicated in autoimmunity. The mechanisms of how MDA5 contribute to autoimmunity remain unclear. Here we provide direct evidence that dysregulation of MDA5 caused autoimmune disorders. We established a mutant mouse line bearing MDA5 mutation by ENU mutagenesis, which spontaneously developed lupus-like autoimmune symptoms without viral infection. Inflammation was dependent on an adaptor molecule, IPS-1, indicating the importance of MDA5-signaling. In addition, intercrossing the mutant mice with type I IFN receptor-deficient mice ameliorated clinical manifestations. This MDA5 mutant could activate signaling in the absence of its ligand, but was paradoxically defective for ligand- and virus-induced signaling, suggesting that the mutation induces a conformational change in MDA5. In humans, mutations of MDA5 and RIG-I were found in patients of Aicardi-Goutieres syndrome and Singleton-Merton syndrome. These findings provide insight into the association between disorders of the innate immune system and autoimmunity.

ID: 8 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Akiko Iwasaki
The mucosal surfaces represent major sites of entry for numerous infectious agents. Consequently, the vast mucosal surfaces are intricately lined with cells and lymphoid organs specialized in providing protective antibody and cellular immunity. Our laboratory’s goal is to understand how immunity is initiated and maintained at the mucosal surfaces that serve as natural portals of entry for pathogens of significant health concerns in the world. In this study, we focused on understanding how viruses are recognized by the innate immune system and how that information is used to generate protective immunity. The myxovirus resistance protein 1 (Mx1) is a dynamin-like GTPase that blocks primary transcription of influenza presumably by binding to viral nucleoproteins. Many inbred laboratory mouse strains have mutations in the Mx1 gene including the C57BL/6 mice. By using mice that have intact Mx1, we demonstrate the critical role of innate sensors in viral control. Further, we reveal a lethal consequence of triggering caspase-1 activation in the absence of innate resistance. Therefore, our results demonstrate that caspase-1 in the absence of antiviral resistance can trigger lethal disease and such conditions may underlie vulnerability to IAV disease in humans.

ID: 9 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Caetano Reis e Sousa
Direct sensing of pathogen components is a major trigger of dendritic cell (DC) activation, leading to innate and adaptive immunity. Over the years, we have studied multiple pattern-recognition pathways that mediate DC activation. One pathway for sensing infection by RNA viruses involves recognition of viral genomes or virallyinfected cells in endosomal compartments and utilises members of the toll-like receptor (TLRs) family, including TLR9, 7, or 3. Viral genomes can additionally be recognised in the cytosol by DExD/H-box helicases such as RIG-I, which are activated by RNAs bearing 5’ tri- and di-phosphates. Finally, a distinct pathway involves cell surface and phagosomal recognition of fungi by C-type lectins, which signal via Syk kinase. Notably, we have recently found that some Syk-coupled C-type lectins are involved in functions other than microbial recognition by DC. One, CLEC-2, allows DCs to relax lymph node stromal cells, permitting expansion of lymph nodes upon inflammation. Another, DNGR-1, allows DCs to detect dead cells by binding exposed F-actin and facilitates cross-presentation of dead cell-associated antigens. Interestingly, DNGR-1 marks CD8 α + DCs, a specialised subtype of DCs in mice and their human equivalents. DNGR-1 additionally can be used to fate map DCcommitted precursors in mouse to define DCs by ontogeny. These studies help build a global picture of the receptors and signalling pathways that regulate DC activation and have applications in immunotherapy of cancer and infectious diseases.

ID: 252 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Sun Hur
Efficient host defense against viral infection depends on proper functions of pattern recognition receptors. One such family of receptors consists of RIG-I and MDA5, well-conserved cytoplasmic helicases that detect viral RNAs during infection and activate the type I interferon (IFN) signaling pathway. My laboratory has been investigating the molecular mechanisms by which these receptors recognize viral dsRNAs and elicit the IFN response against a broad range of viruses. In this talk, I will present our discoveries on the oligomerization of these receptors during viral RNA recognition and activation of the downstream adaptor molecule, MAVS. I will also describe our recent findings on the previously unappreciated effector-like functions of these receptors that are mediated by their abilities to remodel viral RNA: protein complexes.

ID: 13 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Stefan Rose-John
Cytokines receptors exist in membrane bound and soluble form. The IL-6/soluble IL-6R complex stimulates target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. We have named this process ’trans-signaling’. The soluble IL-6R is generated via ectodomain shedding by the membrane bound metalloprotease ADAM17. Soluble gp130 is the natural inhibitor of IL-6/soluble IL-6R complex responses. The dimerized recombinant soluble gp130Fc fusion protein is a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R responses. Interestingly, depending on the animal model used, global blockade of IL-6 signaling by neutralizing monoclonal antibodies and selective blockade of IL-6 trans-signaling can lead to different consequences. We used neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the sgp130Fc protein for selective blockade of IL-6 trans-signaling in several animal models of human diseases. Inhibition of IL-6 trans-signaling but not global IL-6 blockade was beneficial in the cecal ligation and puncture sepsis model. Defense against bacterial infections rely on the membrane bound IL-6R. Acute pancreatitis often results in subsequent acute lung injury, which is an inflammatory disease with high mortality. IL-6 is necessary for the inflammatory process to reach the lung and blockade of IL-6 trans-signaling is sufficient to block the disease. The extent of inflammation is controlled by trans-signaling via the soluble IL-6R. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate in animal models of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis, pancreatitis, lupus erythematodes, colon cancer, ovarian cancer, pancreatic cancer, nephrotoxic nephritis and high fat diet induced obesity that IL-6 trans-signaling via the soluble IL-6R is the crucial step in the development and the progression of the disease. Therefore, sgp130Fc is a novel therapeutic agent for the treatment of chronic inflammatory diseases and cancer and it underwent phase I clinical trials as an anti-inflammatory in 2013/2014. Phase II clinical trials in patients with autoimmune diseases such as inflammatory bowel disease will follow in 2015/16.

ID: 11 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Michael Malim
Mike’s laboratory utilises molecular genetic, cultured cell, biochemical and structural, bioinformatic and cohort-based methodologies to study the biological principles that underpin HIV replication and pathogenesis (AIDS). Current areas of interest include host-virus interactions, cell-encoded mechanisms of anti-viral resistance and virus particle assembly. Over the last ten years, much of his group’s work has been devoted to the viral protein Vif; and it was through these efforts that the human anti-HIV gene APOBEC3G was recognised and characterised. More recently, his group identified the interferon-induced gene MX2 as a novel mediator of resistance to HIV infection that suppresses virus entry into the nucleus.

ID: 253 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Harmit Malik
We have dissected the evolutionary history of host-virus interactions between primate genomes and various viruses including retroviruses, poxviruses and polyomaviuses. Our evolution-guided functional virology approach has revealed not just an ancient history of genetic conflicts facing primate antiviral genes, but also the means to identify the specificity domains by virtue of signatures of rapid evolution. We highlight the use of such approaches to identify multiple, independently acting antiviral specificiaty domains in the primate antivial Mx GTPase proteins. These case studies of antiviral genes have revealed many common ‘evolutionary rules’ of genetic adaptation, using which it may be possible to even infer the action of past viral infections, even those that may not have left imprints in host genomes – a form of indirect ‘paleovirology’ (study of ancient viruses). More recently, we have discovered that one previously unappreciated form of viral adaptation is via ‘gene-accordions’ that facilitate acquisition of adaptive alleles.

ID: 14 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): David Artis
Employing models of microbial colonization, pathogen infection, chronic inflammation and tissue repair, research in the Artis lab is examining how mammalian host genetics and signals derived from the environment and commensal microbial communities influence innate and adaptive immune cell responses. We are employing gnotobiotic mice to examine the influence of defined commensal microbial communities on intestinal and peripheral immune cell development, function and influence on tissue homeostasis. Our recent findings indicate that commensal microbes have a significant regulatory influence on lymphocyte, innate lymphoid cell and granulocyte function associated with susceptibility to multiple infectious, inflammatory and metabolic disease processes. It is hoped that the results of these studies will advance understanding of the pathophysiology of multiple chronic inflammatory diseases, including asthma, allergy, inflammatory bowel disease and obesity, and provide a framework to test new therapeutic pathways to prevent and treat these diseases.

ID: 15 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Alan Sher, L. Antonelli, C. Feng, D. Costa, B. Andrade, A O’Garra, K. Mayer-Marber
In addition to their well known anti-viral functions, Type I IFN’s and their associated genes have been shown to enhance certain bacterial infections. These observations have led to the concept that the positive vs negative effects of Type I IFN in infection may be context dependent and in the case of bacterial diseases such as tuberculosis and listeriosis raise the possibility of targeting Type IFN as an approach to therapy. Focusing on M. tuberculosis infection, I will summarize recent data on the association of Type I IFN with active disease, the mechanism(s) of bacterial induced Type I IFN production as well as the pathways by which the cytokine suppresses bacterial control. Finally, I will discuss strategies for targeting this regulatory loop, focusing on our recent work in which eicosanoid manipulation was used to suppress Type-I IFN dependent progression of acute tuberculosis. This project received support from the intramural research program of the NIAID, NIH, USA.

ID: 177 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Glen Barber
We have recently reported that STING (stimulator of interferon genes) is essential for controlling Toll-Like Receptor (TLR)-independent, cytosolic DNA-mediated innate immune signaling. Accordingly, STING appears essential for protecting the host against lethal disease following infection by pathogens such as HSV1. Such cellular DNA sensors may also play a key role in triggering inflammation aggravated autoimmune diseases. Autoimmune diseases such as Aicardi-Goutieres syndrome (AGS) are characterized by the overproduction of cytokines such as type I interferon (IFN) suggesting that stimulation of host innate immune responses, speculatively by chronic infection or self-nucleic acids, play a role in the manifestation of these diseases. It is known that mice lacking DNAse II die during embryonic development through comparable inflammatory disease since phagocytosed DNA from apoptotic cells cannot be adequately digested and intracellular host DNA sensors are activated resulting in the production of a variety of cytokines including type I IFN. However, we have found that STING controls innate immune signaling events that facilitate such events. DNase II-dependent autoimmune embryonic lethality was rescued by loss of STING function and polyarthritis completely prevented since cytosolic DNA failed to robustly trigger cytokine production through STING controlled signaling pathways. Consequently, loss of STING expression similarly alleviated Trex-1-dependent lethal inflammatory myocarditis is mice, a model for AGS, speculatively caused by endogenous self DNA. Our data provides molecular insight into the causes of DNA-mediated inflammation-dependent autoimmune disorders as well as inflammation driven cancer and affords a new target that could plausibly be therapeutically controlled, to help prevent such diseases.

ID: 261 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Robert G. Korneluk
The Inhibitor of Apoptosis (IAP) family members are important oncogenes overexpressed in many solid and blood cancers. We have recently found that innate immune stimulants such as oncolytic viruses, TLR agonists and vaccines can potently synergize with a class of IAP-antagonist drugs known as Smac mimetic compounds, or SMCs, in various models of cancer [Beug et al., Nature Biotechnology 32: 182–90, 2014]. SMCs target and cause the degradation of the cellular inhibitors of apoptosis, cIAP1 and cIAP2, to specifically sensitize tumor cells to death signals from the immune system such as TNF α or TRAIL. Both cIAP1 and cIAP2 are ubiquitin ligases, with overlapping functions, which mediate signaling by all members of the TNF superfamily. The proteasomal-mediated degradation of cIAP1 and cIAP2 by SMCs alter immune-mediated signaling of various pathways controlled by these IAPs. SMCs are currently in early phase cancer clinical trial development and are well tolerated but show limited efficacy as monotherapy. However, in combination with immune stimulants, SMCs potently induce the bystander killing of tumor cells, which is attributable to a type I IFN dependent production of the proinflammatory cytokines TNF α and TRAIL. The approach is extremely effective in eradicating orthotopic models of mouse solid and blood cancers, including breast, glioblastoma and multiple myeloma. We propose that Smac mimetics will greatly improve the efficacy of oncolytic virus, and other immunotherapies, in the clinic.

ID: 84 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Tadatsugu Taniguchi
When we initiated our studies on the molecular characterization of cytokines, namely type I interferons and interleukins, the conventional wisdom was that they are molecules secreted upon induction of gene transcription and translation by variety of stimuli. It was in this context that we also discovered a gene family for transcription factors, termed interferon regulatory factors (IRFs). IRFs have become a large focus in terms of their contribution in immunity and oncogenesis. In recent years, we focused our study on a new class of cytokine-like molecule, High-mobility group box protein 1 (HMGB1) that function in and out of the cell exerting seemingly unrelated biological activities. We present recent data showing the critical modifications of HMGB1 for its versatile functions, in particular, for the regulation of inflammation and tumor development. We also present recent results that show for how Dectin family of innate receptors contributes to anti-tumor responses, in which IRF5 activation is involved in part. The series of these finding will also be discussed in terms of cancer therapy.

ID: 155 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Markus Heim
An estimated 70% of individuals infected with hepatitis C virus (HCV) develop chronic hepatitis (CHC) that can lead to cirrhosis and hepatocellular carcinoma. The innate immune system is central to host-virus interactions during the entire natural course of the disease. The viral escape mechanisms that result in persistent infections are poorly understood. In vitro, The HCV NS3/4A protease efficiently cleaves and inactivates two important signaling molecules in the sensory pathways that react to HCV pathogen associated molecular patterns (PAMPs) to induce interferons (IFNs), i.e. mitochondrial anti-viral signaling protein (MAVS) and Toll-IL-1 receptor domain-containing adaptor inducing IFN- β (TRIF). Despite this well documented viral escape mechanism, in vivo the innate immune system reacts to HCV within the first days after infection by inducing a strong IFN type I/III response. After 4–8 weeks, HCV specific T cells are recruited to the liver. IFN- γ stimulated genes get strongly expressed in the liver. In about 30% of patients the virus is eliminated during the acute phase of the infection by T cell mediated anti-viral mechanisms. In the remaining 70% of patients, HCV persists for decades. During this phase, T cell derived IFN- γ cannot be detected any more in liver biopsies. Instead, in about half of the patients, hundreds of type I or III IFN stimulated genes become again strongly expressed. However, this innate immune reaction is ineffective against HCV. Moreover, patients with constitutive IFN stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN- α (pegIFN- α ) and ribavirin. The viral escape mechanisms that protect HCV from IFN mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cells with refractory IFN signal transduction pathways or to cell compartments that are not accessible to anti-viral IFN stimulated effector systems. Recently, genetic variations in the IFN- λ 4 gene locus were found to be strongly associated to spontaneous clearance of HCV and to response to treatment with pegIFN- α and ribavirin. The finding supports a central role of the innate immune in host-viral interactions. The signaling pathways and cellular interactions that link genetic variants of IFN- λ 4 with immune answers to HCV remain to be elucidated.

ID: 180 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Rune Hartmann
Humans has 4 IFN λ genes, but nevertheless both spontaneous and treatment induced clearance of HCV specifically depend upon genetic variation within the IFNL4 gene. The IFN λ 4 protein signals through the canonical IFN λ receptor complex and full transcriptome analysis did not reveal any significant differences in the gene induction patterns between IFN λ 3 and IFN λ 4. However, we demonstrated that an amino acid substitution of a proline to a serine at position 70 (P70S) in the IFN λ 4 protein substantially altered its antiviral activity. Paradoxically the lower antiviral activity of the S70 version of IFN λ 4 leads to improved prognosis for HCV infected patients. Patients harboring the impaired IFN λ 4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared to patients coding for the fully active IFN λ 4-P70 variant. Our data provide compelling evidence that the active IFN λ 4 protein is the cause of poor HCV clearance through a mechanism that we do not yet fully understand but which involves the interferon activity of this protein. One aspect where IFN λ 4 clearly distinguishes itself from the remaining isoforms of IFN λ is the poor secretion rate. Preliminary data suggest that the poor secretion of IFN λ 4 is a phenotype restricted to primates. We are currently studying the molecular cause of the impaired secretion of IFN λ 4 and exactly when this phenotype was introduced.

ID: 147 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Cem Gabay
For content of presentation see main article published in the special issue of CYTOKINE.

ID: 150 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Markus Neurath
Cytokines play a crucial role in the pathogenesis of inflammatory bowel diseases (IBD). IBD comprise to different disorders: Crohn’s disease and ulcerative colitis. These diseases are characterized by chronic diarrhea, abdominal pain and weight loss and place a significant burden on the affected patients. Cytokines control multiple aspects of the inflammatory response in IBD by binding to their specific cognate receptors on the surface of intestinal target cells. Additionally, cytokines reaching the systemic circulation have been implicated in driving extraintestinal symptoms of IBD (e.g. arthritis). In the inflamed mucosa in IBD, the balance between pro-inflammatory and anti-inflammatory cytokines is altered and pro-inflammatory cytokines dominate the cytokine milieu. This situation impedes the resolution of inflammation and instead leads to disease perpetuation and tissue destruction in IBD. Based on these observations, it is no surprise that anti-cytokine agents have been considered for therapy of IBD. While anti-TNF agents are now used in clinical routine for IBD therapy, other new anti-cytokine agents such as anti-IL12/IL-23 antibodies are on the horizon. Moreover, multi-cytokine blockers such as JAK inhibitors have been recently used in pilot studies for IBD therapy. In this presentation, the role of cytokines in IBD and the current status of anti-cytokine therapy will be reviewed.

ID: 156 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Andreas Diefenbach
Innate lymphoid cells (ILCs) are a recently discovered family of innate lymphocytes that are substantially represented at mucosal surfaces and have been implicated in the protection of epithelial barriers. Various types of ILCs can be discriminated based on the expression of distinct transcription factors controlling the expression of a distinct set of cytokine genes endowing the various ILC subsets with a specific range of effector functions. Currently, three groups of ILCs are being recognized. Group 1 ILCs (ILC1s) are a diverse group of ILCs comprised of natural killer (NK) cells and other, poorly defined subsets of ILCs. It is believed that the ILC1 fate decision is controlled by the T-box transcription factor T-bet endowing ILC1s with the capability to produce large amounts of IFN- γ . ILC2s express high levels of GATA-3, produce IL-5 and IL-13 and have been involved in immunity to helminth infections and in the pathogenesis of allergic diseases. Group 3 ILCs developmentally depend on the transcription factor ROR γ t and produce the cytokines IL-22, IL-17A and IL-17F. ILC3s are believed to be involved in the protection against intestinal bacterial infections and, if inappropriately stimulated, can be important drivers of inflammatory disorders. The transcriptional programs and effector cytokines of the various ILC subsets strikingly resemble those of the various T helper cell effector fates suggesting that such transcriptional circuitry already formed in the evolutionary older innate immune system. The various ILC subsets are developmentally related as all ILC lineages depend on the transcriptional regulator Id2 (inhibitor of DNA binding 2) that interfers with E2 protein-controlled gene expression. This raises the important issue if ILCs may derive from a common ILC progenitor (CILP). Identification of such a progenitor would allow to identify the molecular signals required for the specification of the various ILC lineages. I will discuss progress towards our understanding of the molecular programs regulating ILC fate decisions and our current models of transcriptional stability and plasticity of ILC fates. Finally, I will discuss an unprecedented role of ILC3s in the protection against mucosal virus infections. Research in my lab is supported by grants from the European Research Council (ERC) and Deutsche Forschungsgemeinschaft.

ID: 181 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Wenjun Ouyang
IL-22 is an IL-10 family cytokine, which is predominantly produced by T helper subsets and group 3 innate lymphoid cells (ILCs). IL-22 receptor, IL-22R/IL-10R2, however, is preferentially expressed on tissue epithelial cells such as skin keratinocytes and intestinal epithelial cells. IL-22 induces antimicrobial responses from these epithelial cells. In addition, IL-22 helps to preserve epithelial integrity and promote wound healing responses. We show that IL-22 participates in skin wound healing. In a diabetic wound healing model that mimics the delayed wound healing in diabetic foot ulcer, IL-22 facilitates the healing responses. Similar wound healing response is also observed in the intestine. IL-22 reduces epithelial damage in DSS induced colitis model. Importantly, IL-22 exerts indispensable roles in mucosal immunity. IL-22 can regulate the expression of proinflammatory cytokine, IL-18, in the ileum. IL-18 conversely also promotes IL-22 production from ILCs and Th cells. Interestingly, metabolic disorders compromise mucosal immunity which is associated with reduced IL-22 production. Exogenous IL-22 not only enhances mucosal immunity in diabetic db/db mice, but also improves many metabolic parameters including glucose tolerance and insulin responses.

ID: 172 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Hergen Spits, Bernink Jochem, Suzannea Bal, Xari Romero Ros
Innate lymphoid cells represent a family of lymphocytes that play important roles at the cross road between innate immunity, adaptive immunity and tissue repair and modeling. Most subsets of this family remained under the radar because of their rarity and the existence of these cells was uncovered only recently. ILC are classified in three groups on the basis of cytokine production profile and dependency on transcription factors. In my presentation I will show data on the role of ILC2 in inflammatory diseases in humans. These cells depend on GATA3 for their function and promptly produce type 2 cytokines like IL-5 and IL-13 following activation with cytokines like IL-25, Il-33 and TSLP. ILC2 accumulate in inflamed nasal tissue in Chronic Rhinosinusitis. In another airway inflammatory disease Chronic Pulmonary Obstructive Disease (COPD) ILC2 are decreasing dependent on the severity of the disease. Evidence will be presented that ILC2 transdifferentiate into IFNgamma producinc ILC1 in COPD. These data along with previously published data about transdifferentiation of ILC3 in inflamed intestines indicate that ILC are highly plastic cells that can adopt different phenotype and function dependent on the microenvironment.

ID: 184 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Daniel J. Cua
The orphan nuclear receptor transcription factor ROR γ t is essential for TGF- β - and IL-6-dependent lineage commitment of Th17 cells. ROR γ t is induced during the CD4 and CD8 double positive stage of T cell receptor selection and is required for their survival and generation of a diverse TCR repertoire. While naïve CD4+ T cell repress ROR γ t expression as they exit the thymus, several populations of innate lymphocytes-including γ δ T cells and innate lymphoid cells (ILC)-maintain ROR γ t expression. These cells migrate to peripheral tissues and serve as immune sentinels controlling the cytokine landscape. They are poised to release IL-17, IL-22, and other inflammatory cytokines because they constitutively express ROR γ t and IL-23R, as well as a range of stress and PRR sensors. The significance of these findings will be discussed in the context of targeting the IL-17 pathway for treatment of auto-inflammatory diseases.

ID: 151 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Andreas Wack, Sophia Davidson, Stefania Crotta, Teresa McCabe, Edith Hessel, Rune Hartmann
Type I and type III interferons (IFN α β and IFN λ ) are key antiviral cytokines. In addition, IFN α β is increasingly recognised as potentially disease-promoting in infection. We explored the roles of these IFN families in influenza infection and as anti-influenza treatment. When comparing influenza-infected 129 to C57BL/6 mouse strains, we found increased lung damage, morbidity and mortality, yet higher levels of IFN α β , in 129 mice than in the more resistant C57BL/6 mice. IFN α β receptor deficiency in 129 mice decreased morbidity and lung damage, and ameliorated immune-mediated tissue damage, indicating that IFN α β levels are a host determinant of influenza severity. In contrast, the respiratory epithelial anti-influenza response was unaffected by IFN α β receptor deficiency, as IFN λ replaced IFN α β in these cells. Lack of IFN α β signalling reduced expression of the death-inducing receptor DR5 on lung epithelia and its ligand TRAIL on inflammatory monocytes, and depletion of PDCA-1+ cells or interruption of TRAIL-DR5 interaction protected infected 129 mice. Therefore, excessive IFN α β signalling in response to acute influenza infection may explain morbidity. Our results suggest that humans with propensity to strong IFN α β signalling may be at risk of severe influenza. We assessed the implications of our results for influenza treatment, using C57BL/6 mice with a functional Mx1 allele. Treatment with either IFN α 4 or IFN λ 2 prior to infection blocked influenza replication and protected against host morbidity and mortality. In contrast, outcome of IFN treatment during influenza infection was divergent. Results of IFN therapy will be presented and discussed in the context of treatment options for influenza in humans.

ID: 159 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Susanne Herold
Influenza A viruses (IAV) may cause lung injury and acute respiratory distress syndrome (ARDS) characterized by apoptotic injury to the alveolar epithelium and accumulation of excessive fluid (edema) in the alveolar airspaces resulting in loss of barrier function, respiratory failure, and death. We recently demonstrated that inflammatory macrophages recruited from the circulation into the alveoli substantially contribute to influenza-induced lung epithelial injury by IFN-dependent expression of pro-apoptotic factors such as TNF-related apoptosis-inducing ligand (TRAIL). Following severe injury, clearance of excess edema fluid, driven by the alveolar epithelial Na, K-ATPase, is crucial for survival of patients with ARDS. We demonstrate that, apart from causing direct injury to the delicate alveolar barrier, macrophage mediators significantly impair resolution of inflammation in terms of edema clearance from the infected lungs. Using ex vivo and in vivo infection models including transgenic mice and adoptive cell transfer strategies, we identify a paracrine cell communication network between alveolar epithelial cells and alveolar macrophages leading to decreased alveolar epithelial Na, K-ATPase plasma membrane abundance and inhibition of alveolar fluid clearance. Our data furthermore reveal that therapeutic blockade of this cellular cross-talk improves edema resolution which is of clinical significance to patients with IAV-induced lung injury.

ID: 169 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Friedemann Weber
Release of nucleocapsids into the cytoplasm is one of the first steps of virus infection. At this initial stage, viral copy numbers are low and the nucleocapsids are especially vulnerable to host cell defences. The group of negative-stranded RNA viruses with a segmented genome (s-NSVs) contains several important pathogens like influenza virus (family Orthomyxoviridae), Rift Valley fever virus (genus phlebovirus, family Bunyaviridae), or Lassa virus (family Arenviridae). We have previously shown that the “panhandle” promoter of incoming s-NSV nucleocapsids is recognized by RIG-I, the main cytoplasmic pathogen sensor for RNA viruses. On one hand, this triggers antiviral signalling and IFN induction as expected. On the other hand, however, the clamping of RIG-I onto the “panhandle” promoter can exert a direct inhibitory effect on virus propagation. In my presentation, I will sum up these findings, present virus countermeasures, and expand the concept of immediate early nucleocapsid recognition beyond RIG-I.

ID: 82 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Curt Horvath
The detection of RNA virus infections triggers the production type I interferon (IFN), and is a major component of the powerful antiviral system that directly interferes with virus replication and contributes to both innate and adaptive immune responses. Virus replication intermediates such as double stranded RNA (dsRNA) or RNAs with distinct non-self modifications are recognized in the cytoplasm by pattern recognition receptors including RIG-I, MDA5, and LGP2. These innate sensors recognize non-self RNAs via their C-terminal domains, and RIG-I and MDA5 use N-terminal CARDs to induce the activation of the downstream signaling scaffold, MAVS. MAVS coordinates the assembly of signaling machinery including TRAFs and IKK-family kinases that activate IRF3 and NFkB transcription factors. Available evidence suggests LGP2 acts as a concentration dependent switch to regulate RLR antiviral signaling. For positive actions, LGP2 uses its unique catalytic activity to enhance MDA5 RNA recognition, dsRNA filament assembly, and enable more efficient activation of MAVS and downstream signal transduction. The mechanism of LGP2 negative regulation have been investigated, and results indicate that LGP2-mediated inhibition occurs downstream of RIG-I, MDA5, and MAVS. LGP2 inhibition does not require ATPase activity or RNA binding. Instead, results indicate that LGP2 targets TRAF signaling proteins, disengaging their ubiquitin ligase activity, and potently preventing NFkB activation in MAVS dependent and independent systems. Identification of TRAF proteins as inhibitory targets not only resolves the dual roles of LGP2 in antiviral signaling regulation, but also expands the potential impact of LGP2 negative regulation beyond innate antiviral signaling.

ID: 165 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Klaus Pfeffer, Daniel Degrandi, Elisabeth Kravets
IFN γ is an immunomodulatory cytokine that rapidly activates potent host cell effector mechanisms to confront a variety of intracellular pathogens. Some of the most abundantly IFN γ induced proteins are the 65-kDa guanylate-binding proteins (GBPs), which mediate cell-autonomous immunity. GBPs are related to the dynamin super family of GTPases and are highly conserved throughout the vertebrate lineage. The human genome harbors seven GBPs and at least one pseudogene, whereas the mouse genome contains 11 GBPs and two pseudogenes. The gene loci of murine GBPs (mGBPs) are tandemly organized in clusters on chromosomes 3 and 5. GBPs contain a conserved GTPase-domain which binds guanine nucleotides with low affinities. This induces nucleotide dependent GBP multimerization and cooperative hydrolysis of GTP via GDP to GMP. Some GBPs are isoprenylated, endowing them with the ability to associate with intracellular membranous compartments. Murine GBPs (mGBPs) exert a major impact on cell-autonomous restriction of Toxoplasma gondii . T. gondii is an apicomplexan protozoan parasite with a broad host range, is distributed worldwide and causes serious and often fatal infections in immunocompromised hosts. T. gondii infection experiments in mice deficient for mGBP1 or mGBP2 prove that mGBPs are essential immune effector molecules mediating antiparasitic resistance. In several cell types distinct mGBPs accumulate at the parasitophorous vacuole membrane (PVM) of T. gondii . The translocation of mGBPs to the PVM is accompanied by depletion of cytosolic vesicle like structures (VLS), formation of large multimers at the PVM, subsequent loss of PVM integrity, followed by a direct assault of mGBP2 upon the plasma membrane of the parasite. These findings provide important dynamic and molecular insights into the function of cell-autonomous immunity.

ID: 189 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Sen C. Ganes, Volker Fensterl
IFITs, the interferon-induced proteins with tetratricopeptide repeats, are encoded by a family of interferon (IFN)-stimulated genes. There are four human IFITs and three mouse Ifits, whose primary structures are related but distinct. They are strongly induced by both Type I and Type III IFNs; in addition, TLR, RLR or STING signaling pathways, that activate IRFs, can induce these genes without any involvement of IFN. IFITs do not have any known enzyme activities and hence, their cellular activities are mediated by altering the functions of specific cellular proteins and RNAs to which they bind. Recent derivation of Ifit knock-out mouse lines has paved the way for studying their role in viral pathogenesis and such studies have revealed the nature of their antiviral effects in vivo, which are not only virus-specific but tissue-specific as well. Moreover, viruses often use elegant means to evade the actions of Ifits, thereby demonstrating the importance of these proteins’ antiviral functions. It is anticipated that future investigation of additional properties of the Ifit KO mice will reveal new biological functions of these proteins.

ID: 163 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Etty Benveniste, Hongwei Qin, Ashley Harms, David Standaert
Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the CNS, characterized by inflammation, demyelination and axonal damage. Cells of the innate (macrophages, microglia, neutrophils) and adaptive (T-cells, B-cells) immune system contribute to both the pathology and repair of MS. Parkinson’s Disease (PD) is a neurodegenerative disease characterized by the deterioration of motor activities that are controlled by the nigrostriatal system. The motor symptoms of PD result from the progressive and selective loss of dopaminergic (DA) neurons in the midbrain substantia nigra pars compacta. Additionally, the PD brain is characterized by cytoplasmic and neuritic fibrillar α -synuclein ( α -syn) inclusions (known as Lewy bodies (LB) and Lewy neurites (LN), respectively). Recently, an impressive number of publications have implicated inflammation as a major pathogenic factor in PD, with involvement of both innate and adaptive immune cells. MS and PD are characterized by abundant production of cytokines that activate and regulate the functions of immune and glial cells. The Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is the major signaling system utilized by cytokines, and is critical for development, regulation and termination of innate and adaptive responses. Dysregulation of the JAK/STAT pathway has pathological implications for a number of autoimmune and neuroinflammatory diseases. We have documented aberrant activation of the JAK/STAT pathway in pre-clinical models of both MS and PD. We will discuss the efficacy of inhibitors of the JAK pathway, known as Jakinibs, in these pre-clinical models, and describe the mechanisms that underlie their beneficial effects on neuroinflammation and neurodegenerative responses.

ID: 186 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Ari Waisman, Tommy Regen, Ilgiz Mufazalov, Judith Hauptmann
In the past years, and clear pathogenic role was shown for Th17 cells in the development of autoimmune diseases. In particular, these cells were shown to play a critical roIn the past years, and clear pathogenic role was shown for Th17 cells in the development of autoimmune diseases. In particular, these cells were shown to play a critical role in the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. One of the major cytokines Th17 cells produce is IL-17A, a cytokine of the IL-17 family. IL-17A, as well as it homologue IL-17F bind and trigger cells via the IL-17 receptor A/C complex. We have used a series of mice with deficiencies in the production of IL-17, IL-17 receptor or the transcription factors responsible for Th17 differentiation to understand the role of IL-17 and Th17 in autoimmune CNS disease. Insights into the function of IL-17 in autoimmunity will be presented.

ID: 149 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Katrin Mayer-Barber
Cytokines such as IL-1 and type I IFNs and lipid mediators, such as eicosanoids, play key roles in regulating the balance between host-detrimental and host-beneficial immune responses and as such represent important targets for immunologic intervention. Thus, redirecting the outcome of the host immune response from induction of disease to pathogen control based on our growing understanding of the cytokine and lipid mediator networks governing these processes could lead to novel treatment strategies for infectious diseases. We found that during tuberculosis, type I IFN driven inflammation exacerbates disease and renders mice highly susceptible to infection. In contrast, induction of type I IFNs during pulmonary fungal infection with Cryptococcus resulted in enhanced control of infection. Thus, modulating the type I IFN pathway in pulmonary infections caused by non-viral pathogens can lead to both enhanced or diminished host resistance and thus represents a potent immunotherapeutic target. I will summarize our recent data that revealed pivotal intersections between the IL-1 and type I IFN cytokine pathways and eicosanoids in the host response to mycobacteria and how targeting this cross talk can promote resistance to lethal M. tuberculosis infection and be potential exploited to design host-directed therapies.

ID: 154 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Sarah Gaffen
The cytokine IL-17 came into prominence a decade ago with the discovery of Th17 cells. IL-17 signals through its receptor to control immune responses to extracellular pathogens, particularly fungi. Conversely, IL-17 activates pathology in many autoimmune and infectious settings. Therefore, constraint of the IL-17 receptor pathway is an essential facet of its regulation. To date, our understanding of IL-17 signaling checkpoints remains quite limited, but in recent years a number of negative regulators have been identified. These inhibitors block IL-17 activation at multiple levels, although the integration of these inhibitors remains poorly understood. This talk will discuss emerging work defining several novel feedback inhibitors that restrict the downstream IL-17 signaling pathway and their molecular mechanisms of action.

ID: 185 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Andreas Pilchmair
Virus infection leads to drastic changes in the abundance and interaction profile of cellular proteins. These changes are partially dependent on the ability of cells to sense and fend off viruses and on the function of viral open reading frames that actively perturb antiviral signaling pathways. In sum these changes contribute to the pathogenicity of viruses. We are using a combination of hypothesis-driven approaches combined with unbiased mass spectrometry and transcriptional profiling to study specific signaling pathways as well as the general ability of proteins to interact with each other after virus infection or stimulation with type-I interferons.

ID: 251 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Kyung Hyun Yoo, Ha Youn Shin, Sumin Oh, Lothar Hennighausen
The sole purpose of the mammary gland is the production of milk and during lactation more than 95% of the mRNA in secreting epithelial cells is contributed by less than 10 genes. Control relays regulating these genes are characterized by two astounding features, their ability to activate expression more than 10,000-fold during pregnancy and prevent regulatory spillover to neighboring genes. Studies in our laboratory focus on the critical roles of the common cytokine-inducible transcription factor (TF) STAT5 and the chromatin factor CTCF in the establishment of mammary-specific enhancers and the organization of regulatory chromatin domains that prevent regulatory spillover of these powerful enhancers to neighboring genetic loci. Through ChIP-seq experiments we defined the entirety of mammary enhancers in the mouse genome. These enhancers are characterized by the presence of H3K27ac and the joint binding of the TFs STAT5, GR, NFIB and MED1. CRISPR/CAS9 gene editing in mice was used to explore the role of defined STAT5 binding sites in the establishment and function of mammary-specific enhancers. Notably, STAT5 is the pioneer factor in the establishment and function of a subset of mammary enhancers. CTCF ChIP-seq experiments established putative chromatin boundaries of mammary-specific genetic islands. Using CRISPR/CAS9 CTCF sites within and surrounding mammary-specific islands were mutated in mice and their functional significance in establishing mammary-restricted gene regulation was investigated.

ID: 2 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Curdin Conrad, Jeremy Di Domizio, Alessio Mylonas, Cyrine Belkhodja, Olivier Demaria, Alexander Navarini, Anne-Karine Lapointe, Lars French, Maxime Vernez, Michel Gilliet
Paradoxical psoriasis is a well-known side-effect of anti-TNF therapy affecting 2–5% of treated patients. As this side effect often necessitates cessation of the anti-TNF therapy, there is an urgent need to understand its pathogenesis. Here, we analyzed a series of 25 cases of paradoxical psoriasis induced by all anti-TNF agents available. Underlying diseases, clinical presentation and histological patterns varied considerably among patients. However, we found a striking, uniform, and selective upregulation of type I interferons (IFN) in skin of paradoxical psoriasis as compared to classical psoriasis. The overexpression of type I IFN was paralleled by a massive accumulation of plasmacytoid dendritic cells (pDCs) within the skin. In-vitro, TNF blockade directly enhanced type I IFN production by pDCs, while TNF itself inhibited its production suggesting a crossregulation of TNF and pDC-derived type I IFN. In a skin injury mouse model, anti-TNF therapy increased and sustained type I IFN expression and skin infiltration by pDCs and was sufficient to induce a psoriatic phenotype in a type I IFN-dependent manner. Our study demonstrates that anti-TNF therapy unleashes unabated type I IFN production by pDCs, thereby inducing a psoriasis-like skin phenotype. Thus, we unravel the pathomechanism of paradoxical psoriasis and provide a clinical relevance for the crossregulation of TNF and type I interferon.

ID: 16 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Imene Soufli, Ryma Toumi, Hayet Rafa, Manel Amri, Chafia Touil-Boukoffa
Inflammatory bowel disease is less common in countries where there is a greater risk of exposure to helminths. In our study, we examined the modulatory effect of the laminated layer extracted from the cyst wall of a helminth parasite, Echinococcus granulosus , on dextran sulfate sodium (DSS)-induced colitis in mice. Crude extract of E. granulosus laminated layer was injected intra-peritoneally daily, starting 3 days before colitis induction. The Disease Activity Index was monitored daily and histological scores were evaluated. Nitric oxide (NO) and cytokine levels (interferon γ (IFN- γ ) , tumor necrosis factor α (TNF- α ) and interleukin 10 (IL-10)) were assessed. In addition, the colonic expression of inducible nitric oxide synthase (iNOS) and nuclear factor- κ B (NF- κ B) was examined. Importantly, our results indicate that hydatid laminated layer pretreatment significantly improved the clinical symptoms and histological scores observed during DSS-induced colitis. Furthermore, treatment with hydatid laminated layer caused a significant decrease in NO (^∗∗ p < 0.001 ), IFN - γ (^∗ p < 0.01) and TNF- α production (^∗ p < 0.05) and an increase in IL-10 production. These results were associated with localized down-regulation of iNOS and NF- κ B expression. Our results demonstrate the potent protective effect of hydatid laminated layer in DSS induced colitis through downregulation of IFN- γ and TNF- α and up regulation IL-10 production. Furthermore, hydatid laminated layer played a beneficial role in maintaining the integrity of the intestinal mucosal barrier against DSS-induced injury suggesting the crucial role of helminth in immuno-protection against IBD.

ID: 17 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Sarah Pogue, Tetsuya Taura, Mingying Bi, Glen Mikesell, Yong Yun, Angela Sho, Collette Behrens, Maxwell Stevens, Teresa Domagala, Maya Sokolovsky, Hussein Hallak, Moti Rosenstock, Anthony Doyle, David Wilson
Many cytokines have potential therapeutic applications and several, including type I interferons (IFN), have been approved for the treatment of cancer and/or autoimmune disease. While these agents are effective, they are associated with dose-limiting toxicities that prevent their use at levels sufficient to promote optimal therapeutic benefit. Thus, approaches which enhance the therapeutic index (TI) of cytokines are needed. A moderate degree of tumor-specificity may be achieved by attaching a cytokine such as IFN to a tumor-targeting antibody; such immunocytokines are highly active but show only moderate tumor-specificity since the cytokine is still active on antigen-negative cells. We sought to improve the TI of antibody-targeted cytokines by mutating the cytokine portion to significantly reduce its affinity for its receptor, thereby making it dependent on antibody-targeting. Here we demonstrate that such molecules, consisting of attenuated cytokines (Attenukines™) attached to tumor-targeting antibodies, are 1000–100,000-fold more potent on antigen-positive cells compared to antigen-negative (normal) cells. This is shown for antibody-Attenukine™ fusion proteins based on multiple tumor antigens (CD20, CD38, CD138, HMW-MAA, HLA) and multiple attenuated mutants of IFN, IFN, IL-4 and IL-6. Furthermore, we have evaluated an anti-CD38-attenuated IFN molecule (anti-CD38-Attenukine™) in various CD38+ myeloma xenograft models and found that this molecule retains potent specific anti-tumor efficacy. Moreover, in non-human primates, we have confirmed that the attenuating mutation in IFN indeed decreases non-targeted IFN biomarker responses by greater than 100-fold. Our findings suggest that the administration of antibody-attenukines™ to cancer patients may promote robust cytokine-dependent tumor-killing while minimizing systemic toxicity.

ID: 18 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Haiyan Jia, Paula Dilger, Chris Bird, Meenu Wadhwa
IL-27 is a pleiotropic cytokine of the IL-6/IL-12 family with diverse biological functions. Previous in vivo studies have suggested the anti-tumour activities of IL-27 in animal models, whereas clinical observations indicate the link of IL-27 in tumour progression. IL-27 has recently been shown to cause inhibition of proliferation on primary leukemic cells from paediatric patients, but information on its role in human leukemic cell lines is limited. In the present study, we investigated the ability of IL-27 to regulate cell growth and survival of various human leukemic cell lines. Our results showed that in human leukemic cell lines coexpressing both IL-27R chains IL-27R α and gp130, IL-27 did not inhibit cell growth, but caused a dose-dependent proliferation of the acute myeloid leukemic cell line OCI-AML5, and the erythroleukemic cell lines, TF-1, UT-7 and UT7/EPO. Consistent with this, IL-27 promoted cell survival and reduced TNF- α -induced apoptosis of the leukemic cell lines. IL-27 also decreased the sensitivity of the leukemic cells to chemotherapeutic drugs cytarabine and daunorubicin. We observed that IL-27 induced the activation of STAT1/3 and ERK1/2 in the leukemic cells. Growth stimulation by IL-27 was suppressed by the specific MEK inhibitor U0126 and the PI3K inhibitor wortmannin, suggesting that IL-27-induced cell proliferation is mediated via the activation of two distinct pathways of MAPK/ERK and PI3K/AKT. The present study is the first demonstration of the proliferative property of IL-27 in human leukemic cell lines, suggesting that IL-27 may play an unfavourable role in tumour growth of certain subtypes of human leukaemia.

ID: 19 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Chul-Soo Cho, In-Woon Baek, Ki-Jo Kim, Wan-Uk Kim
Interactions between keratinocyte and dermal fibroblast via paracrine loop play an important role in wound repair and keloid formation. In this study, we investigated heparanase expression in activated keratinocyte, and tested its effect on the survival of dermal fibroblasts. Plasma heparanase levels were measured in scleroderma patients, and heparanase expression was evaluated in the skin of bleomycin-induced fibrosis mice and HaCaT keratinocyte (HaCaT). Dermal fibroblasts were cocultured with HaCaT separated by transwell insert under serum starvation, and apoptosis was determined using APOPercentage assay. Plasma heparanase levels were significantly higher in 26 scleroderma patients than in 10 healthy subjects, and positively correlated with plasma TGF- β levels. In bleomycin-induced fibrosis mice, increased heparanase expression was observed in keratinocyte layer, but not in dermal layer. Treatment of HaCaT with hypoxia resulted in significant increase in heparanase expression, and this increase was accompanied by concomitant increase of matrix metalloproteinase-9, both of which are known to degrade epidermal basement membrane components. Coculture of dermal fibroblasts and HaCaT in the presence of hypoxia significantly protected the apoptosis of dermal fibroblasts induced by serum starvation, but it was abolished by anti-heparanase antibody or transfection of HaCaT with heparanase siRNA. Dermal fibroblasts cocultured with HaCaT exposed to hypoxia exhibited increased Akt phosphorylation, and pretreatment of dermal fibroblasts with LY294002, an inhibitor of phosphatidylinositol 3-kinase, significantly abolished anti-apoptotic effect of heparanase on dermal fibroblasts. These data indicate that hypoxia, caused possibly by microvascular alteration, increases heparanase production in keratinocytes, which may promote fibrosis in scleroderma by inhibiting the apoptosis of dermal fibroblasts.

ID: 20 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Pierre Génin, Frédérique Cuvelier, Sandrine Lambin, Josina Côrte-Real Filipe, Elodie Autrusseau, Christine Laurent, Emmanuel Laplantine, Robert Weil
Viral invasion into a host is initially recognized by the innate immune system, mainly through activation of the intracellular cytosolic signaling pathway and coordinated activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF- κ B) transcription factors that promote type I interferon gene induction. The TANK-binding Kinase 1 (TBK1) phosphorylates and activates IRF3. We now show that Optineurin (Optn) dampens the antiviral innate immune response by targeting the deubiquitinating enzyme CYLD to TBK1 in order to inhibit its enzymatic activity. Importantly, we found that this regulatory mechanism is abolished at the G2/M phase as a consequence of the nuclear translocation of CYLD and Optn. As a result, we observed, at this cell division stage, an increased activity and phosphorylation of TBK1 that lead to its relocalization to mitochondria and to enhanced interferon production, and activation of the antiviral innate immune response before cells enter into mitosis. Overall our study shows that the antiviral immune system is controlled during the cell cycle and that Optineurin-mediated induction of this system might serve to protect cells from infections that eventually occur during cell division.

ID: 21 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Yoshio Ishibashi, Susumu Kitanaka, Yuji Asahara
Crude extracts from Ganoderma lucidum , a medical mushroom, are popularly used for treatment of allergic diseases such as atopic dermatitis (AD). Triterpenes are the major active constituents of Ganoderma lucidum . Stimulation of protease-activated receptor-2 (PAR2) on cutaneous keratinocytes induces secretion of various immune and inflammatory cytokines including interleukin 8 (IL8), and thereby plays a role in the development of allergic skin inflammation. Thus, PAR2-mediated signaling has been suggested to be a therapeutic target for the treatment of allergic diseases. This study aimed to evaluate the inhibitory effects of Ganoderma triterpenes on PAR2-mediated IL8 secretion from human keratinocytes. Normal human epidermal keratinocytes (NHEK) were stimulated with PAR2-activating peptide (AP) in the presence or absence of Ganoderma triterpenes in vitro. IL8 secretion from NHEK cells was measured by enzyme-linked immunosorbent assay (ELISA). Chemical structures of triterpenes were determined based on spectroscopic evidence and mass spectral data. Among of Ganoderma triterpenes, ganolucidate F exhibited most potent inhibitory activity on PAR2-mediated IL8 secretion from keratinocytes (IC50 = 12.5 μ M). Ganolucidic acid γ a showed strong inhibitory activity with IC50 value of 29.1 μ M. In addition, ganoderic acid η and ganoderic acid θ showed remarkable inhibitory effects with IC50 values of 64.9 μ M and 109.5 μ M, respectively. Elucidation of relationships between chemical structure of triterpenes and inhibitory activity implied that substitution of hydroxy group at C-23, instead of a carbonyl group, may be a very important structural feature for inhibitory activity. Ganoderma lucidum -derived ganoderic acids could be a candidate drug for treatment of allergic skin diseases.

ID: 22 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Ghizlane Maarifi, Mohamed Ali Maroui, Jacques Dutrieux, Laurent Dianoux, Sébastien Nisole, Mounira K. Chelbi-Alix
Interferons (IFNs) orchestrate immune defense through induction of hundred of genes. Small ubiquitin-like modifier (SUMO) is involved in various cellular functions, but little is known about its role on IFN responses. Prior work identified SUMOylation of STAT1 as an important mode of regulation of IFN γ signaling. Here, we investigated the various roles of SUMO in IFN signaling, transcriptional response and IFN-induced biological effects. We first show that SUMO overexpression leads to STAT1 SUMOylation and to a decrease in IFN-induced STAT1 phosphorylation. This process correlates with lower levels of STAT1 binding to GAS in response to IFN γ , while the binding of an ISGF3-like complex to ISRE in response to IFN α is not altered. Interestingly, IFNs exert a negative retro-control on their own signaling by enhancing STAT1 SUMOylation. Furthermore, we show that expression of each SUMO paralog selectively inhibits IFN γ -induced IP-10 and TAP1 mRNA expression. Importantly, inhibition of IFN γ signaling by SUMO is associated with a decrease of IFN γ -induced apoptosis and cell growth inhibition as well as a dramatic reduction of IP-10-induced chemotaxis. Conversely, inhibition of SUMOylation results in a higher IFN γ -induced STAT1 phosphorylation and biological responses. In conclusion, our work thus allows the inclusion of SUMO to the list of negative regulators of IFN signaling known to date and posits SUMO as a possible contributor to IFN γ resistance.

ID: 23 [Cytokine]

Thu, 01 Oct 2015 17:12:36 +0000

Publication date: November 2015
Source:Cytokine, Volume 76, Issue 1
Author(s): Ghizlane Maarifi, Mohamed Ali Maroui, Laurent Dianoux, Sébastien Nisole, Mounira K. Chelbi-Alix
SUMOylation is the post-translational covalent but reversible conjugation of SUMO to proteins. In human, the SUMO protein family consists of SUMO1 and two highly homologous proteins SUMO2 and SUMO3 (collectively called SUMO2/3), which cannot be distinguished by currently available antibodies. We have shown that SUMO overexpression leads to STAT1 SUMOylation and to a decrease in IFN-induced STAT1 phosphorylation resulting in an inhibition of IFN γ -induced transcription without affecting that of IFN α . Here, we focused on the IFN-induced gene products associated with PML nuclear bodies and we show that in SUMO3-expressing cells, neither IFN α nor IFN γ could increase PML and Sp100 protein expression, as they enhanced their SUMO3 conjugation and subsequent proteasomal degradation. Since it is known that SUMO3 is important for the recruitment of RNF4, a poly-SUMO-dependent E3 ubiquitin ligase implicated in PML degradation in arsenic-treated cells, we went on to show that RNF4 depletion in IFN-treated HeLa-SUMO3 cells prevented PML degradation, thus restoring an increase of PML and Sp100 protein expression in response to IFN. In addition, SUMO3, but not SUMO1, overexpression reduced the capacity of IFN to inhibit viral proteins and EMCV production. These results are consistent with the degradation of PML in IFN-treated HeLa-SUMO3 cells, and with our previous observation that PML depletion decreases the anti-EMCV effect of IFN (Maroui et al., J Virol 2011). Altogether, our results uncover a new role for SUMO3 in the modulation of both type I and type II IFN responses.