Member Of IL-1 Family Research Articles

Possible association of proinflammatory cytokine IL-19 gene polymorphism with psoriasis

Background: Interleukin (IL-19) a member of the IL-10 family involved in abnormal keratinocyte differentiation and proliferation which is the hall mark of psoriasis. Aim: The aim of this study was to investigate the association between IL-19 gene polymorphism in patients with chronic plaque psoriasis as a factor in the susceptibility and development of psoriasis. Subjects and Methods: 200 psoriatic patients and 200 controls were genotyped for three IL-19 polymorphic sites by Amplification Refractory Mutation System polymerase chain reaction (ARMS-PCR). Results: Our results demonstrated that polymorphism of IL-19-42232 C/A (rs2243188) adjusted* OR=0.59; (95% CI=0.25 – 1.40)and IL-19-38386 T/C (rs2073186) adjusted* OR=1.28; (95% CI=0.70 – 2.35) does not show any significant association with risk of psoriasis while as IL-19 -35402 G/C (rs2243158) adjusted* OR=2.05; (95% CI=1.19 – 3.55) was found to be in association with increased risk of psoriasis. HT3 ACG OR=0.41; (95% CI=0.20- 0.84) haplotype is associated with decreased risk of psoriasis. Limitations: Small sample size. A large epidemiological study is required to confirm these findings. Family based studies and association studies of different populations are required to confirm the impact of IL-19 in genetic predisposition of psoriasis. Conclusion: IL-19 polymorphism have considerable role towards the susceptibility of psoriasis in north Indian population. Evaluating the role of IL-19 cytokine in pathogenesis of psoriasis will prove supportive for the development of psoriasis management.

Interleukin-35 as an Emerging Player in Tumor Microenvironment.

IL-35 is the newest member of IL-12 family. A dimeric protein consisting of two separate subunits has manifested suppressive actions on immune system, which is counterproductive in the context of cancers. Various reports have confirmed its inhibitory role on immune system which is carried out via formation of IL-35-producing regulatory T cells (iTr35), increased Treg development and suppressive Th17 cells growth. Although last decade has seen a great deal of scientific interest on this subject, the exact role, precise signal transduction and elaborative functions of IL-35 in tumor microenvironment (TME) remained elusive. Search for anti-IL-35 therapies have exhibited limited success in animal models. Contrarily, few studies have denied the idea that IL-35 plays a role in cancer. The purpose of this review is to analyze the reported scientific data on continuous symphony of IL-35 in cancers since the inception of former.

Expression and Purification of Tag-removed Human IL37 by Digestion on Beads in Escherichia coli.

Human Interleukin 37 (IL37), a unique anti-inflammatory cytokine of IL1 family member, plays critical roles in innate and adaptive immunity and inflammation. Preparation of high purity and tag-removed recombinant IL37 protein (rIL37) is critical for its clinical application. In this study, we constructed an N-terminal cleavable GST-fused IL37 expression vector for recombinant expression. Subsequent to transformation and optimization of the induction temperature, the soluble expression level of rIL37 was 306.5 mg/L of culture medium at 18 °C induction in Escherichia coli. Meanwhile, rIL37 was digested on beads by GST-HRV3C protease during GST affinity chromatography. After further purification, the purity of rIL37 was higher than 99 %. Finally, the antiinflammatory activity of tag-removed protein was verified by the results showing that rIL37 suppressed IL1β production in PBMCs. This work presents a protocol to produce high purity and tag-removed rIL37 with antiinflammatory activity, which provides the firm basis for advancing clinical application in human IL37-related inflammatory diseases.

IL-36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis.

Psoriasis vulgaris (PV) results from activation of IL-23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin-derived pro-inflammatory cytokines, IL-36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL-23 and IL-36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL-23-induced mouse model of psoriasiform dermatitis by functional inhibition of IL-36 receptor (IL-36R) was interrogated. Anti-mouse IL-36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL-36α-induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL-36α systemic injection in mice. In addition, anti-IL-36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL-36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL-36 signalling in IL-23/Th17 pathway, the ability of anti-IL-36R mAbs to inhibit skin inflammation in an IL-23 ear injection model was assessed. Inhibiting the IL-36 pathway resulted in significant attenuation of skin thickening and psoriasis-relevant gene expression. Taken together, these data suggest a role for IL-36 signalling in the IL-23/Th17 signalling axis in PV.

Contribution of IL-33 to the Pathogenesis of Colorectal Cancer.

The development of colorectal cancer (CRC) is not only determined by transformed cells per se, but also by factors existing in their immune microenvironment. Accumulating scientific evidence has revealed that interleukin (IL)-33, an IL-1 family member, plays an essential role in the regulation of immune response and is relevant in CRC pathogenesis. Data from both human and experimental studies demonstrated that IL-33 inhibits host anti-tumor immunity, remodels tumor stroma and enhances angiogenesis, thereby promoting the development of CRC. These pro-tumor effects of IL-33 are mainly mediated by IL-33 receptor ST2 (also known as IL-1RL1). Based on those findings, it is currently hypothesized that the IL-33/ST2 pathway is a potential biomarker and therapeutic target for colorectal tumorigenesis. Herein, we summarize the recent discoveries in understanding the critical role of the IL-33/ST2 pathway in contributing to the pathogenesis of colorectal tumorigenesis and discuss its potential implications for the future development of effective anti-tumor strategies.

The Pleiotropic Immunomodulatory Functions of IL-33 and Its Implications in Tumor Immunity.

Interleukin-33 (IL-33) is a IL-1 family member of cytokines exerting pleiotropic activities. In the steady-state, IL-33 is expressed in the nucleus of epithelial, endothelial, and fibroblast-like cells acting as a nuclear protein. In response to tissue damage, infections or necrosis IL-33 is released in the extracellular space, where it functions as an alarmin for the immune system. Its specific receptor ST2 is expressed by a variety of immune cell types, resulting in the stimulation of a wide range of immune reactions. Recent evidences suggest that different IL-33 isoforms exist, in virtue of proteolytic cleavage or alternative mRNA splicing, with potentially different biological activity and functions. Although initially studied in the context of allergy, infection, and inflammation, over the past decade IL-33 has gained much attention in cancer immunology. Increasing evidences indicate that IL-33 may have opposing functions, promoting, or dampening tumor immunity, depending on the tumor type, site of expression, and local concentration. In this review we will cover the biological functions of IL-33 on various immune cell subsets (e.g., T cells, NK, Treg cells, ILC2, eosinophils, neutrophils, basophils, mast cells, DCs, and macrophages) that affect anti-tumor immune responses in experimental and clinical cancers. We will also discuss the possible implications of diverse IL-33 mutations and isoforms in the anti-tumor activity of the cytokine and as possible clinical biomarkers.

Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer.

The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control ofimmune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly,distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease.

Serum interleukin-37 level and interleukin-37 gene polymorphism in patients with Behçet disease.

Behçet's disease (BD) is a chronic inflammatory disease. The etiopathogenesis of BD is not well understood and several cytokines and genetic factors have been investigated. Interleukin (IL)-37, which a member of IL-1 family is an anti-inflammatory cytokine. The aim of the study was to analyze serum IL-37 level and IL-37 gene polymorphisms to assess its possible role in BD. Two hundred twenty-three patients with BD and 80 healthy controls (HC) were enrolled. Serum IL-37 level was measured using an enzyme-linked immunosorbent assay (ELISA). Deoksiribo Nucleic acids (DNA) were extracted using a genomic DNA isolation kit. Single nucleotide polymorphism (SNP) of IL-37 gene (rs3811047) was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR/RFLP) methods. Serum IL-37 level was not significantly different in BD and HC (p > 0.05). Serum IL-37 level was not associated with the disease activity (p > 0.05). However, its level was higher in mucocutaneous involvement compared with systemic involvement (p = 0.002) and HC (p = 0.005). IL-37 gene polymorphisms were similar in BD and HC (p > 0.05). IL-37 may play a role in the etiopathogenesis of BD by contributing to manifestation with more moderate clinical symptoms.

IL-20 receptor cytokines in autoimmune diseases.

IL-19, IL-20, and IL-24 are the members of IL-10 family. They are also known as IL-20 receptor (IL-20R) cytokines as they all signal through the IL-20RA/IL-20RB receptor complex; IL-20 and IL-24 (but not IL-19) also signal through the IL-20RB/IL22RA1 receptor complex. Despite their protein structure homology and shared use of receptor complexes, they display distinct biological functions in immune regulation, tissue homeostasis, host defense, and oncogenesis. IL-20R cytokines can be expressed by both immune cells and epithelial cells, and are important for their interaction. In general, these cytokines are considered to be associated with pathogenesis of chronic inflammation and autoimmune diseases, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. However, a number of studies also highlighted their suppressive functions in regulating both innate and adaptive T cell responses and other immune cells, suggesting that the role of IL-20R cytokines in autoimmunity may be complex. In this review, we will discuss the immunobiological functions of IL-20R cytokines and how they are involved in regulating autoimmune diseases.

Beyond the TNF-α Inhibitors: New and Emerging Targeted Therapies for Patients with Axial Spondyloarthritis and their Relation to Pathophysiology.

Axial spondyloarthritis (axSpA) is a complex disease that affects the joints and entheses of axial and peripheral joints, and is associated with inflammation in extra-articular sites such as the gut. Improved knowledge on genetics and immunology has improved treatment options with the availability of treatments targeting tumor necrosis factor-α (TNF-α) and interleukin (IL)-17. However, these agents do not provide clinical benefit for about 40% of patients, and additional therapeutic options are necessary. Theories on pathogenesis includes misfolding of HLA-B*27 during its assembly leading to endoplasmic reticulum stress and autophagy/unfolded protein response (UPR). HLA-B*27 may express free heavy chain on the cell surface, which activates innate immune receptors on T, natural killer, and myeloid cells with pro-inflammatory effects. Activation of UPR genes is associated with increased TNF-α, interleukin-23 (IL-23), IL-17, interferon-γ expression, and expansion of T helper (Th)-17 cells. Certain genotypes of endoplasmic reticulum aminopeptidase (ERAP) 1 and 2 are associated with ankylosing spondylitis (AS) and functionally interact with the HLA-B27 peptidome. Innate immune cells type 3, which express RORγt, regulate expression of IL-17 and IL-22 in T cells. Stimulation of gamma-delta T cells with IL-23 also induces IL-17. Mucosa-associated invariant T cells residing in the gut mucosa express IL-17 in AS patients after stimulation with IL-7. Prostaglandin E2 induces IL-17A independent of IL-23 via IL-1β and IL-6. The pathogenic role of gut inflammation, zonulin and microbiota, which has a different composition in AS patients, remains to be elucidated. This article also includes a comprehensive review on the mechanism of action and efficacy of the biological treatments currently approved for axSpA (TNF-α inhibitors and IL-17 inhibitors) and future targets for treatment (other IL-17 family member (s), Janus kinase, IL-23, and phosphodiesterase 4).

Critical role of inflammatory mast cell in fibrosis: Potential therapeutic effect of IL-37.

Fibrosis involves the activation of inflammatory cells, leading to a decrease in physiological function of the affected organ or tissue. To update and synthesize relevant information concerning fibrosis into a new hypothesis to explain the pathogenesis of fibrosis and propose potential novel therapeutic approaches. Literature was reviewed and relevant information is discussed in the context of the pathogenesis of fibrosis. A number of cytokines and their mRNA are involved in the circulatory system and in organs of patients with fibrotic tissues. The profibrotic cytokines are generated by several activated immune cells, including fibroblasts and mast cells (MCs), which are important for tissue inflammatory responses to different types of injury. MC-derived TNF, IL-1, and IL-33 contribute crucially to the initiation of a cascade of the host defence mechanism(s), leading to the fibrosis process. Inhibition of TNF and inflammatory cytokines may slow the progression of fibrosis and improve the pathological status of the affected subject. IL-37 is generated by various types of immune cells and is an IL-1 family member protein. IL-37 is not a receptor antagonist; it binds IL-18 receptor alpha (IL-18Rα) and delivers the inhibitory signal by using TIR8. It has been shown that IL-37 can be protective in inflammation and injury, and inhibits both innate and adaptive immunity. IL-37 may be useful for suppression of inflammatory diseases induced by inhibiting MyD88-dependent TLR signalling. In addition, IL-37 downregulates NF-κB induced by TLR2 or TLR4 through a mechanism dependent on IL-18Rα. This review summarizes current knowledge on the role of MC in inflammation and tissue/organ fibrosis, with a focus on the therapeutic potential of IL-37-targeting cytokines.

Meta-analysis of RNA sequencing datasets reveals an association between TRAJ23, psoriasis, and IL-17A.

Numerous studies of relatively few patients have linked T cell receptor (TCR) genes to psoriasis but have yielded dramatically conflicting results. To resolve these discrepancies, we have chosen to mine RNA-Seq datasets for patterns of TCR gene segment usage in psoriasis. A meta-analysis of 3 existing and 1 unpublished datasets revealed a statistically significant link between the relative expression of TRAJ23 and psoriasis and the psoriasis-associated cytokine IL-17A. TRGV5, a TCR-γ segment, was also associated with psoriasis but correlated instead with IL-36A, other IL-36 family members, and IL-17C (not IL-17A). In contrast, TRAJ39 was strongly associated with healthy skin. T cell diversity measurements and analysis of CDR3 sequences were also conducted, revealing no psoriasis-associated public CDR3 sequences. Finally, in comparison with the expression of TCR-αβ genes, the expression of TCR-γδ genes was relatively low but mildly elevated in psoriatic skin. These results have implications for the development of targeted therapies for psoriasis and other autoimmune diseases. Also, the techniques employed in this study have applications in other fields, such as cancer immunology and infectious disease.

Perivascular adipose tissue dysfunction aggravates adventitial remodeling in obese mini pigs via NLRP3 inflammasome/IL-1 signaling pathway.

Perivascular adipose tissue (PVAT), a special type of adipose tissue, closely surrounds vascular adventitia and produces numerous bioactive substances to maintain vascular homeostasis. PVAT dysfunction has a crucial role in regulating vascular remodeling, but the exact mechanisms remain unclear. In this study, we investigated whether and how obesity-induced PVAT dysfunction affected adventitia remodeling in early vascular injury stages. Mini pigs were fed a high sugar and fat diet for 6 months to induce metabolic syndrome and obesity. In the mini pigs, left carotid vascular injury was then generated using balloon dilation. Compared with normal mini pigs, obese mini pigs displayed significantly enhanced vascular injury-induced adventitial responses, evidenced by adventitia fibroblast (AF) proliferation and differentiation, and adventitia fibrosis, as well as exacerbated PVAT dysfunction characterized by increased accumulation of resident macrophages, particularly the M1 pro-inflammatory phenotype, increased expression of leptin and decreased expression of adiponectin, and production of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Primary AFs cultured in PVAT-conditioned medium from obese mini pigs also showed significantly increased proliferation and differentiation. We further revealed that activated nod-like receptor protein 3 (NLRP3) inflammasome and its downstream products, i.e., IL-1 family members such as IL-1β and IL-18 were upregulated in the PVAT of obese mini pigs; PVAT dysfunction was also demonstrated in preadipocytes treated with palmitic acid. Finally, we showed that pretreatment with IL-1 receptor (IL-1R) antagonist or IL-1R knockdown blocked AF proliferation and differentiation in AFs cultured in PVAT-conditioned medium. These results demonstrate that obesity-induced PVAT dysfunction aggravates adventitial remodeling after early vascular injury with elevated AF proliferation and differentiation via activating the NLRP3/IL-1 signaling pathway.

Study of interleukin-18 during antiviral therapy for hepatitis C with sofosbuvir, ribavirin, and interferon in Menoufia hospitals

Objectives The objectives of this study were to evaluate the role of interleukin-18 (IL-18) in liver cirrhosis caused by hepatitis C, and to determine the effect of the triple regimen treatment sofosbuvir, ribavirin, and interferon on its serum levels. Background IL-18 is a member of the IL-1 family. Recent studies have suggested that IL-18 plays a role in the pathogenesis of liver damage during acute and chronic hepatitis; furthermore, IL-18 may be involved in the development and progression of liver fibrosis. Patients and methods The present study was carried out on 27 hepatitis C patients and 15 age-matched and sex-matched healthy individuals. All patients were subjected to history taking, complete medical examination, and laboratory investigations for liver and kidney functions. Serum levels of IL-18 were measured by ELISA three times for each patient: the first one was measured before treatment initiation, the second after 1 week of treatment, and the third was measured after 3 months of treatment. Results The serum levels of IL-18 were highly elevated in hepatitis C patients compared with controls (P Conclusion There is significant elevation in the serum levels of IL-18 in hepatitis C patients. IL-18 concentrations were reduced following a successful course of antiviral treatment.

Mast cells participate in allograft rejection: can IL-37 play an inhibitory role?

The aim of this study was to evaluate the role of mast cells (MCs) in allograft rejection, eventually inhibited by IL-37. Immune cells including MCs participate in allograft rejection by generating IL-1, IL-33, TNF and other cytokines. We evaluated allograft rejection on the experience of our experimental data and using the relevant literature. MCs are involved in initiation and regulation of innate and adaptive immune responses-pathways. MCs are important pro-inflammatory cells which express high-affinity receptor FceRI and can be activated by IgE and some pro-inflammatory cytokines, such as IL-1 and IL-33. The cross-linkage of high affinity IgE receptor on MCs by antigen ligation has a crucial role in allergy, asthma, anaphylaxis, cancer and allograft rejection. MCs mediate immunity in organ transplant, leading to the activation of allospecific T cells implicated in the rejection and generate pro-inflammatory cytokines/chemokines. IL-1 pro-inflammatory cytokine family members released by MCs mediate allograft rejection and inflammation. IL-37 is also an IL-1 family member generated by macrophage cell line in small amounts, which binds to IL-18Rα and produces an anti-inflammatory effect. IL-37 provokes the inhibition of TLR signaling, TLR-induced mTOR and (MyD88)-mediated responses, suppressing pro-inflammatory IL-1 family members and increasing IL-10. IL-37 inhibition offers the opportunity to immunologically modulate MCs, by suppressing their production of IL-1 family members and reducing the risk of allograft rejection, resulting as a potential good therapeutic new cytokine. Here, we report the relationship between inflammatory MCs, allograft rejection and pro-inflammatory and anti-inflammatory IL-37.

The IL-33 Receptor ST2 Regulates Pulmonary Inflammation and Fibrosis to Bleomycin.

Idiopathic pulmonary fibrosis is a progressive, devastating, and yet untreatable fibrotic disease of unknown origin. Interleukin-33 (IL-33), an IL-1 family member acts as an alarmin with pro-inflammatory properties when released after stress or cell death. Here, we investigated the role of IL-33 in the bleomycin (BLM)-induced inflammation and fibrosis model using mice IL-33 receptor [chain suppression of tumorigenicity 2 (ST2)] mice compared with C57BL/6 wild-type mice. Unexpectedly, 24 h post-BLM treatment ST2-deficient mice displayed augmented inflammatory cell recruitment, in particular by neutrophils, together with enhanced levels of chemokines and remodeling factors in the bronchoalveolar space and/or the lungs. At 11 days, lung remodeling and fibrosis were decreased with reduced M2 macrophages in the lung associated with M2-like cytokine profile in ST2-deficient mice, while lung cellular inflammation was decreased but with fluid retention (edema) increased. In vivo magnetic resonance imaging (MRI) analysis demonstrates a rapid development of edema detectable at day 7, which was increased in the absence of ST2. Our results demonstrate that acute neutrophilic pulmonary inflammation leads to the development of an IL-33/ST2-dependent lung fibrosis associated with the production of M2-like polarization. In addition, non-invasive MRI revealed enhanced inflammation with lung edema during the development of pulmonary inflammation and fibrosis in absence of ST2.

IL-37 isoform D downregulates pro-inflammatory cytokines expression in a Smad3-dependent manner

IL-37 is a new member of IL-1 family and possesses five different isoforms (named as IL-37 a–e). IL-37b has been demonstrated as a physiological suppressor of immune responses. However, the function of other isoforms remains unknown. Here, we show that IL-37d possesses anti-inflammatory roles both in vitro and in vivo. Firstly, IL-37d is expressed in peripheral blood mononuclear cells (PBMCs) and umbilical cords-derived mesenchymal stem cells (UCMSCs). Secondly, IL-37d overexpression markedly inhibits IL-1β-induced IL-6 production in A549 cells. Consistently, bone marrow-derived macrophages (BMDMs) from IL-37d transgenic mice express low levels of pro-inflammatory cytokines (such as IL-6 and TNF-α) following LPS stimulation, compared with those from wild-type mice. Furthermore, IL-37d transgenic mice produce less pro-inflammatory cytokines, and show much less degree of LPS-induced endotoxemia in vivo. Mechanistically, IL-37d interacts with Smad3 and promotes nuclear translocation of pSmad3. SIS3 (a specific Smad3 inhibitor) treatment completely blocks the inhibitory effects of IL-37d. Thus, our data indicate that IL-37d is a functional cytokine that negatively regulates pro-inflammatory cytokines expression in a Smad3-dependent manner.

Targeting interleukin-22 for cancer therapy

ABSTRACTInterleukin-22 (IL-22) is a member of IL-10 family of cytokines. IL-22 induces proliferative and anti-apoptotic signaling pathways and production of anti-microbial molecules that enhance tissue regeneration and host defense. IL-22 has also been identified as a cancer-promoting cytokine since deregulation of the IL-22-IL-22R1 system is linked to different cancer entities including lung, breast, gastric, pancreatic and colon cancers. T cells and innate lymphoid cells are the main cellular sources of IL-22. Expression of its specific receptor IL-22R1 is restricted to the non-hematopoietic cells which makes the IL-22-IL-22R1 pathway an attractive target for anti-cancer therapy. For development of such therapies, a better understanding of IL-22 regulation in the tumor microenvironment is needed. We could recently decipher how cancer cells promote IL-22 production by memory T cells via induction of IL-1. Here we will discuss how this knowledge might contribute to developing therapies disregulating the IL-22 pathway for cancer immunotherapy.

A Guide to IL-1 family cytokines in adjuvanticity.

Growing awareness of the multiplicity of roles for the IL-1 family in immune regulation has prompted research exploring these cytokines in the context of vaccine-induced immunity. While tightly regulated, cytokines of the IL-1 family are normally released in response to cellular stress and in combination with other danger-/damage-associated molecular patterns (DAMPs), triggering potent local and systemic immune responses. In the context of infection or autoimmunity, engagement of IL-1 family receptors links robust innate responses to adaptive immunity. Clinical and experimental evidence has revealed that many vaccine adjuvants induce the release of one or multiple IL-1 family cytokines. The coordinated release of IL-1 family members in response to adjuvant-induced damage or cell death may be a determining factor in the transition from local inflammation to the induction of an adaptive response. Here, we analyse the effects of IL-1 family cytokines on innate and adaptive immunity with a particular emphasis on activation of antigen-presenting cells and induction of T cell-mediated immunity, and we address in detail the contribution of these cytokines to the modes of action of vaccine adjuvants including those currently approved for human use.

IL-33 inhibits tumor growth through the activation of anti-tumor CD8+ T cell response in hepatocellular carcinoma

Abstract IL-33 secreted by epithelial cells and activated innate immune cells is a member of IL-1 family with dual-immunological effects. It can induce both type 1 and type 2 immune responses and its function as an alarmin has been well demonstrated. However, the role of IL-33 in the development of hepatocellular carcinoma (HCC) is not clear. Here, we examined the function of IL-33 in various murine HCC models by hydrodynamically injecting either IL-33-expressing tumor cells or IL-33-expressing plasmids into the liver of tumor-bearing mice. Tumor growth was greatly inhibited by IL-33 expression. Similarly, in DEN-induced HCC model, we also demonstrated that IL-33 expression inhibited tumor development. This effect was shown to be dependent on extracellular IL-33 and ST2 expression, because it was diminished in ST2 KO mice. Further study showed there were increased percentages and numbers of CD8+ T cells in both spleen and liver in IL-33-expressing tumor-bearing mice. The percentages and numbers of activated and effector CD4+ and CD8+ T cells were also increased in the liver with IL-33 expression. Moreover, IFN-γ production of the CD8+ T cells was upregulated in both spleen and liver by IL-33. The cytotoxicity of CTLs against tumor cells was also enhanced. Depletion of CD8+ and CD4+T cells diminished the antitumor activity of IL-33, suggesting the anti-tumor function of IL-33 was T cell-dependent. In vitro IL-33 treatment could preferentially expand CD8+ T cells and promote their activation and IFN-γ production. Taken together, we demonstrated in murine HCC models that IL-33 could inhibit tumor development through its interaction with ST2 to promote anti-tumor CD8+ T cell response.