The Cytokine Interleukin 6 (IL-6) as a Neural and Endocrine Regulator

Improving recombinant MVA immune responses: Potentiation of the immune responses to HIV-1 with MVA and DNA vectors expressing Env and the cytokines IL-12 and IFN-gamma

The IL-17 (interleukin 17) family consists of six structurally related pro-inflammatory cytokines, namely IL-17A to IL-17F. These cytokines have garnered significant scientific interest due to their pivotal role in the pathogenesis of various diseases. Notably, a specific subset of T-cells expresses IL-17 family members, highlighting their importance in immune responses against microbial infections. IL-17 cytokines play a critical role in host defense mechanisms by inducing cytokines and chemokines, recruiting neutrophils, modifying T-cell differentiation, and stimulating the production of antimicrobial proteins. Maintaining an appropriate balance of IL-17 is vital for overall health. However, dysregulated production of IL-17A and other members can lead to the pathogenesis of numerous inflammatory and autoimmune diseases. This review provides a comprehensive overview of the IL-17 family and its involvement in several inflammatory and autoimmune diseases. Relevant literature and research studies were analyzed to compile the data presented in this review. IL-17 cytokines, particularly IL-17A, have been implicated in the development of various inflammatory and autoimmune disorders, including multiple sclerosis, Hashimoto's thyroiditis, systemic lupus erythematosus, pyoderma gangrenosum, autoimmune hepatic disorders, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, and graft-versus-host disease. Understanding the role of IL-17 in these diseases is crucial for developing targeted therapeutic strategies. The significant involvement of IL-17 cytokines in inflammatory and autoimmune diseases underscores their potential as therapeutic targets. Current treatments utilizing antibodies against IL-17 cytokines and IL-17RA receptors have shown promise in managing these conditions. This review consolidates the understanding of IL-17 family members and their roles, providing valuable insights for the development of novel immunomodulators to effectively treat inflammatory and autoimmune diseases.

Prognostic Role of IL-6 in POEMS Syndrome

Background: Epidemiological and experimental data suggest a causal link between chronic pancreatitis and pancreatic cancer. The cytokine interleukin 6 (IL6) is upregulated during the course of pancreatitis; moreover, recent studies have shown that the cytokine interleukin 6 (IL6) plays a role in pancreatic cancer initiation and progression. Our goal was to investigate whether IL6 upregulation provides a causal link in pancreatitis-induced carcinogenesis in mice. Methods: We previously described the iKras* mouse as a new model of pancreatic tumorigenesis based on pancreas-specific expression of the oncogenic form of Kras, KrasG12D. By crossing iKras* mice with IL6-deficient mice we have generated iKras*; IL6-/-mice, as well as iKras*; IL6+/-. To induce pancreatitis, we injected the colecistokinin agonis Caerulein administered by intraperitoneal injection. The pancreatic tissue was collected at several time-points for histopathological analysis. In addition, the immune cells infiltrated were analyzed by flow cytometry. Results: 1] IL6 is required for pancreatitis induced PanIN maintenance. PanIN lesions arose from both iKras* and iKras*;IL6-/- mice 3 weeks post-pancreatitis. By 17 weeks after pancreatitis the iKras* pancreata were totally replaced by PanINs; however, iKras*; IL6-/- pancreata appeared atrophic, devoid of PanINs and largely populated by acini. Our data further suggest that, in absence of IL6, epithelial cell survival is affected in PanIN lesions. 2] IL6 is a key regulator of inflammation during carcinogenesis. Flow cytometry analysis revealed that fewer macrophage and myeloid-derived suppressor cells (MDSCs) were recruited to iKras*; IL6-/- pancreata 3 weeks post-pancreatitis. MDSCs have been involved in maintaining an immune-suppressive microenvironment in tumors. 3] Taking advantage of the reversible expression of KrasG12D in iKras* mice, we also show that deletion of IL6 signaling accelerates PanIN reprogramming (ductal to acinar redifferentiation) following Kras* inactivation. 4] Finally, in a set of in vitro 3-dimensional culture experiments, we show that IL6 promotes acinar-ductal metaplasia (ADM)/PanIN formation and progression in acinar clusters embedded in Matrigel. Conclusion: Previous studies had shown that IL6 signaling is required for the development of PanIN lesions in mice. Here, we show that IL6 is essential for PanIN maintenance following induction of acute pancreatitis. Thus, IL6 potentially represents a therapeutic target in pancreatic cancer. Citation Format: Yaqing Zhang, Filip Bednar, Wei Yan, Meredith Anne Collins, Sabita Rakshit, Marina Pasca Di Magliano. IL6 signaling is required for pancreatitis-induced pancreatic intra-epithelial neoplasia progression and maintenance in mice. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A104.

IL-13 in asthma and allergic disease: Asthma phenotypes and targeted therapies

The related cytokines, interleukin-6 (IL-6), oncostatin M (OSM), and leukemia inhibitory factor (LIF) direct the formation of specific heteromeric receptor complexes to achieve signaling. Each complex includes the common signal-transducing subunit gp130. OSM and LIF also recruit the signaling competent, but structurally distinct OSMRbeta and LIFRalpha subunits, respectively. To test the hypothesis that the particularly prominent cell regulation by OSM is due to signals contributed by OSMRbeta, we introduced stable expression of human or mouse OSMRbeta in rat hepatoma cells which have endogenous receptors for IL-6 and LIF, but not OSM. Both mouse and human OSM engaged gp130 with their respective OSMRbeta subunits, but only human OSM also acted through LIFR. Signaling by OSMRbeta-containing receptors was characterized by highest activation of STAT5 and ERK, recruitment of the insulin receptor substrate and Jun-N-terminal kinase pathways, and induction of a characteristic pattern of acute phase proteins. Since LIF together with LIFRalpha appear to form a more stable complex with gp130 than OSM with gp130 and OSMRbeta, co-activation of LIFR and OSMR resulted in a predominant LIF-like response. These results suggest that signaling by IL-6 cytokines is not identical, and that a hierarchical order of cytokine receptor action exists in which LIFR ranks as dominant member.

PU.1 is a unique regulatory protein required for the generation of both the innate and the adaptive immune system. It functions exclusively in a cell-intrinsic manner to control the development of granulocytes, macrophages, and B and T lymphocytes. We demonstrate that mutation of the PU.1 gene causes a severe reduction in myeloid (granulocyte/macrophage) progenitors. PU.1 -/- myeloid progenitors can proliferate in vitro in response to the multilineage cytokines interleukin-3 (IL-3), IL-6 and stem cell factor but are unresponsive to the myeloid-specific cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF and M-CSF. The failure of PU.1 -/- progenitors to respond to G-CSF is bypassed by transient signaling with IL-3. In the presence of IL-3 and G-CSF, PU.1 -/- progenitors can differentiate into granulocytic precursors containing myeloperoxidase-positive granules. Thus PU.1 is not essential for specification of granulocytic precursors, but is required for their further differentiation. The failure of PU.1 -/- progenitors to respond to M-CSF is due to lack of c-fms gene transcription. Transduction of c-fms into PU.1 -/- myeloid progenitors bypasses the block to M-CSF-dependent proliferation but does not induce detectable macrophage differentiation. Therefore, PU. 1 appears to be essential for specification of monocytic precursors. Importantly, retroviral transduction of PU.1 into mutant progenitors restores responsiveness to myeloid-specific cytokines and development of mature granulocytes and macrophages. Thus PU.1 controls myelopoiesis by regulating both proliferation and differentiation pathways.

Repeated Topical Challenge with Chemical Antigen Elicits Sustained Dermatitis in NC/Nga Mice in Specific-Pathogen-Free Condition

To investigate the role of T helper-1 cell (Th1) activation in the induction of proinflammatory cytokine production and cartilage damage by rheumatoid arthritis (RA) synovial fluid mononuclear cells (SFMNC) and the subsequent possible beneficial role of the T helper-2 cell (Th2) cytokine interleukin-4 (IL-4) in the inhibition of this process. SFMNC were stimulated with bacterial antigen (hsp60) to activate Th1 cells. Th1 and Th2 specific cytokine profiles (interferon gamma (IFN gamma) and IL-4) and proinflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF alpha) in the conditioned media were analysed. In addition, the conditioned media were tested for their ability to induce cartilage damage. The same parameters were measured in the presence of IL-4. Stimulation of SFMNC with bacterial antigen resulted in an increase in IFN gamma, IL-1, and TNF alpha production which was accompanied by the induction of cartilage damage. Th1 activation could be inhibited by IL-4 as shown by a reduction of IFN gamma. This was accompanied by a decrease in IL-1 and TNF alpha production and inhibition of cartilage damage. Th1 activation is a possible mechanism by which inflammation in RA joints is enhanced. The Th2 cytokine IL-4 inhibits this Th1 activity and may diminish inflammation and induction of cartilage damage in RA joints.

Vitamin D reduces pain and cartilage destruction in knee osteoarthritis animals through inhibiting the matrix metalloprotease (MMPs) expression

Macrophages play a central role in the balance and efficiency of the immune response and are at the interface between innate and adaptive immunity. Their phenotype is a delicate equilibrium between the M1 (classical, pro-Th(1)) and M2 (alternative, pro-Th(2)) profiles. This balance is regulated by cytokines such as interleukin 13 (IL-13), a typical pro-M2-Th(2) cytokine that has been related to allergic disease and asthma. IL-13 binds to IL-13 receptor α1 (IL13Rα1), a component of the Type II IL-4 receptor, and exerts its effects by activating the transcription factor signal transducer and activator of transcription 6 (STAT6) through phosphorylation. MicroRNAs are short (∼22 nucleotide) inhibitory non-coding RNAs that block the translation or promote the degradation of their specific mRNA targets. By bioinformatics analysis, we found that microRNA-155 (miR-155) is predicted to target IL13Rα1. This suggested that miR-155 might be involved in the regulation of the M1/M2 balance in macrophages by modulating IL-13 effects. miR-155 has been implicated in the development of a healthy immune system and function as well as in the inflammatory pro-Th(1)/M1 immune profile. Here we have shown that in human macrophages, miR-155 directly targets IL13Rα1 and reduces the levels of IL13Rα1 protein, leading to diminished activation of STAT6. Finally we also demonstrate that miR-155 affects the IL-13-dependent regulation of several genes (SOCS1, DC-SIGN, CCL18, CD23, and SERPINE) involved in the establishment of an M2/pro-Th(2) phenotype in macrophages. Our work shows a central role for miR-155 in determining the M2 phenotype in human macrophages.

The cytokines Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF, also known as cachectin) exhibit multiple effects on circulating blood cells and cells of the blood vessel wall. For example, these mediators elicit a coordinated Drogram of functions of endothelial cells (EC) that promotes blood coagulation and thrombosis, and lead to clot stabilization. Furthermore, IL-1 and TNF promote adherence to vascular endothelium of leukocytes of many classes.Thus, these cytokines are likely to be involved in signaling the pathologic changes in blood vessels that characterize a number of inflammatory or infectious processes. These two cytokines were originally isolated frcm activated human mononuclear phagocytes, hence their comnon designation as monokines and the terminology "interleukin". However, recent findings have broadened this concept considerably. It is now clear that many cell types can produce IL-1-1ike activity.Several groups showed that human vascular EC can secrete material that stimulates proliferation of thymocytes incubated with suboptima1 doses of the mitogenic lectin phytohemagglutinin, a typical acitivty of IL-1 (thymocyte costimulation).Two related but distinct genes cloned frcm human peripheral blood monocytes encode IL-1 molecules. In human blood monocytes stimulated with bacterial lioopolysaccharide (LPS) IL-1 beta (pi ∼ 7) is the major form expressed while IL-1 alpha (pi ∼ 5) is the less abundant species secreted by human monocytes under these conditions. We found that EC and smooth muscle cells (SMC) isolated from adult human vessels can express these same IL-1 genes. LPS, a standard stimulus to IL-1 secretion in the monocyte, caused accumulation of IL-1 beta mRNA in both vascular cell types. Endothelial cells frcm adult human vessels also contained IL-1 alpha mRNA when treated with LPS in the presence of cycloheximide and LPS-stimulated smooth muscle cells contained RNA that hybridized with an IL-1 alpha cDNA probe as well. Although both vascular cell types can transcribe these IL-1 genes, the time course of this response differs. LPS induced IL-1 beta mRNA production by SMC maximally at 4-6 hr., whereas maximal IL-1 induction by LPS in EC occured 1 day after initiation of the exposure. Actinanycin D (1 ug/ml) blocked 3H-uridine incorporation into macromolecules by > 95% in both EC & SMC, and prevented the LPS-induced increases in IL-1 mRNA levels in these cells. This result suggests that this potentially injurious stimulus causes IL-1 mRNA accumulation by an increase in rates of transcription. These LPS-induced increases in IL-1 mRNA levels corresponded to production of biologically active IL-1 determined as thymocyte costimulation activity. Interestingly, gel filtration experiments revealed a molecular weight of around 22kD for both SMC and EC-derived IL-1 secreted into culture medium in response to LPS. This molecular weight contrasts with the 17 kD species which is the fully processed product secreted frcm activated human monocytes. A possible explanation for this disparity is that the vascular cells secrete a partially processed intermediate form of mature IL-1. Other stimuli for IL-1 mRNA accumulation and secretion of biological activity include TNF and IL-1 itself. Recombinant human INF (≥ 10 ng/ml) increased IL-1 beta mRNA levels in EC & SMC, and caused the EC & SMC to release IL-1-1 ike thymocyte costimulation activity. Of interest is the recent observation that IL-1 itself can stimulate expression of IL-rl genes in vascular wall cells. Both IL-1 aloha and beta can increase IL-1 beta mRNA content in EC & SMC. Hris observation was confirmed with homogenous IL-1 prepared by recombinant DNA technologies (rIL-1). These findings raise the possibility of a novel positive feedback loop in vascular pathophysiology. We also found that rIL-1 alpha or beta also induced the production of prostaglandin E2 (PGE2) by both vascular SMC & EC. This prostanoid, induced by IL-1, inhibits thymocyte _ proliferation. Thus, IL-1 not only induced its own expression but increased production of this immunosuppressive prostanoid. This mechanism provides a potential negative control loop in regulation of the local immune response in blood vessels. Vie conclude that these cells of the blood vessel wall are a source of the potent vasoregulatory and immune mediators IL-1 alpha and beta. Since IL-1 influences the thrombotic, hemostatic, and fibrinolytic functions of endothelium, as well as other responses to acute injury, our findings suggest novel local control mechanisms that may be important in a variety of pathologic states.

Interleukin 6 and Haemostasis

Tumor necrosis factor receptor (TNFR)-associated factors or (TRAFs) are important mediators of Interleukin-17 (IL-17) cytokine signaling and contribute to driving tissue responses that are crucial for protective immunity but are often implicated in immunopathology. By amplifying tissue immune activity, IL-17 cytokine pathways contribute to maintaining barrier function as well as activation of innate and adaptive immunity necessary for host defense. IL-17 receptors signaling is orchestrated in part, by the engagement of TRAFs and the subsequent unlocking of downstream cellular machinery that can promote pathogen clearance or contribute to immune dysregulation, chronic inflammation, and disease. Originally identified as signaling adaptors for TNFR superfamily, TRAF proteins can mediate the signaling of a variety of intercellular and extracellular stimuli and have been shown to regulate the downstream activity of many cytokine receptors including receptors for IL-1β, IL-2, IL-6, IL-17, IL-18, IL-33, type I IFNs, type III IFNs, GM-CSF, M-CSF, and TGF-β Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I- like receptors, and C-type lectin receptors. This review will focus on discussing studies that reveal our current understanding of how TRAFs mediate and regulate biochemical activities downstream of the IL-17 cytokines signaling.

Neutrophils in cisplatin AKI—mediator or marker?