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Immune thrombocytopenia (ITP) is an autoimmune-mediated disease characterized by decreased platelet counts. Cytokines play important roles in modulating the immune response and are involved in the pathogenesis of many autoimmune diseases. This study aimed at exploring the serum levels of a core set of cytokines that exert immune-regulatory functions in newly diagnosed ITP patients (both before and after treatment) and splenectomized ITP patients. Using the Bio-Plex suspension array system and ELISA, the serum levels of IL-10, IL-21, IL-27, IL-33, IL-35, IL-37, and TGF-β 1 were detected. The data showed that the serum levels of the immune regulatory cytokines IL-10, IL-35, and TGF-β 1 were significantly lower in newly diagnosed ITP patients. Decreased cytokine levels could be improved in patients with a complete response or a response after steroid-based treatment(s). The serum concentrations of TGF-β 1 were positively correlated with the platelet counts both before and after treatment. All the detected immune-regulatory cytokines, except IL-37, showed significantly higher levels in splenectomized ITP patients than pretreatment ITP patients and healthy controls. In conclusion, these data suggest that lower levels of immune-regulatory cytokines are involved in the pathogenesis of ITP and that there is a long-lasting overexpression of immune-regulatory cytokines in ITP patients with splenectomy., (©2021 Society for Leukocyte Biology.)

Background: Hepatitis C virus (HCV) is the leading cause of chronic liver diseases including hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. We aimed to assess serum levels of interleukin (IL)-22, IL-27 and IL-35 in patients with hepatitis C and healthy controls to investigate their possible relationship with viral genotypes and liver enzyme levels., Method: A total of 30 newly diagnosed hepatitis C patients with no history of antiviral therapy and 30 healthy individuals participated in this study. Serum levels of IL-22, IL-27 and IL-35 were determined by ELISA in peripheral blood samples from patients prior to and following treament with pan-genotypic direct-acting anti-viral therapy. Serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were measured to determine any possible association between hepatic enzymes and cytokine serum levels concentrations., Result: The results show elevated serum levels of of IL-35 in HCV-infected patients compared to treated cases and healthy controls, whereas there was no significant difference in IL-22 and IL-27 serum levels among the three groups. Additionally, the cytokine levels were not significantly correlated with certain genotypes and levels of liver enzymes., Conclusion: Our findings indicate a potential role for IL-35 in chronic HCV infection and therapeutic management of patients with hepatitis C infection.

Cytokines exert profound effects on the progression of hematopoietic malignancies such as acute myeloid leukemia (AML). Critical roles of cytokines in the context of inflammation have gained special interest. While pro-inflammatory mediators such as IL-1β, TNF-α and IL-6 tend to increase AML aggressiveness, anti-inflammatory mediators such as TGF-β and IL-10 appear to impede AML progression. Dysregulation of the complex interactions between pro- and anti-inflammatory cytokines in AML may create a pro-tumorigenic microenvironment with effects on leukemic cell proliferation, survival and drug-resistance. This article summarizes current knowledge about the functions of pro- and anti-inflammatory cytokines in AML, their modes of action, and therapeutic interventions with potential to improve clinical outcomes for AML patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Interleukin 35(IL-35), a new IL-12 family cytokine, is consisting of IL-12P35 and Epstein-Barr virus-induced gene 3(EBI3) and is required by regulatory T cells(Tregs) for maximal activity. IL-35 is regarded as a promising new type of anti -inflammatory treatment factor, by the in-vitro and mouse models studies confirmed, although the studies have not been able to elucidate the role of IL-35 in human respiratory allergic disease. This paper describes the IL-35 and respiratory allergic diseases of bronchial asthma, allergic rhinitis and research progress in nasal polyps., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Regulatory T (Treg) cells are essential for maintenance of peripheral tolerance and prevention of autoimmune diseases in part by producing immunosuppressive cytokines. Recently, microRNAs (miRNAs) have also been involved in autoimmune disorders, not least for their crucial role in the regulation of Treg biology and function. We simultaneously investigated the concentration of IL-35, IL-10, TGF-β, and sCD25 in supernatant of cell culture and the expression patterns of several miRNAs in CD4(+)CD25(+) CD127(-/low) FoxP3(+) Tregs of ulcerative colitis (UC) patients. Significantly lower levels of IL-10 and IL-35 were observed in Treg cultures of UC patients. miR-21, miR-146a, and miR-155 levels were downregulated and miR-31 level was upregulated in Tregs of patients. Our results suggest that microRNAs may serve as a novel regulator in function and homoeostasis of UC Treg cells, providing a key role for them in pathophysiology of UC.

Objective: Allergic asthma is a chronic airway inflammation resulting from an imbalance of T helper (Th) cell responses to allergens. Interleukin (IL)-35 has been shown to have potent immunoregulatory properties. Whether IL-35 participates in the immunopathogenesis of allergic asthma patients is still unknown., Methods: CD4+ T cells and CD4+ CD25- T cells were obtained from peripheral blood mononuclear cells (PBMCs) using magnetic separation. The concentration of IL-35 in plasma was measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of the IL-35 subunits, EBI3 and IL-12p35, were detected by quantitative real-time PCR (qPCR). The proliferative responses of CFSE-labeled CD4+ CD25- T cells in the presence or absence of rhIL-35 were evaluated by flow cytometry. Cytokine production of activated CD4+ CD25- T cells was examined by flow cytometry and ELISA., Results: IL-35 protein and mRNA levels were decreased in allergic asthmatics. The frequencies of CD4+ CD25+ Foxp3+ Tregs and CD4+ IL-12p35+ T cells in allergic asthma patients were lower than in healthy controls. Moreover, the addition of rhIL-35 suppressed CFSE+ CD4+ CD25- T cell proliferation in vitro in a dose-dependent manner, and the suppression induced by rhIL-35 was associated with decreases in IL-4 but not IFN-γ and IL-17 production of activated CD4+ CD25- T cells. The increased level of Th1/Th2 was observed in allergic asthmatics in the presence of rhIL-35., Conclusions: Our data suggest that IL-35 can effectively suppress the proliferation and IL-4 production of activated CD4+ CD25- T cells in allergic asthma, and that IL-35 may be a new immunotherapy for asthma patients.

CD4+ T cells and many cytokines play critical roles in the pathogenesis of Guillain-Barré Syndrome (GBS), an immune-mediated inflammatory disease. However, the role of IL-35, a novel member of the IL-12 cytokine family, in this kind of disease has not yet been elucidated. In this study, we investigated the functional changes of CD4+ T cells from GBS patients with IL-35 treatment in vitro. This study involved 21 GBS patients and an equal number of healthy controls (HCs). The results indicated that the average concentration of IL-35 in the plasma of GBS patients was lower than that of healthy controls (HCs). Increased levels of STAT1, STAT3 and STAT4 proteins and T-bet, ROR γt, IFN-γ and IL-17A mRNA were observed in CD4+ T cells from GBS patients. In contrast, the levels of STAT5 and STAT6 proteins and GATA3, Foxp3, IL-4 and TGF-β1 mRNAs were decreased in GBS patients in comparison with those of HCs. In addition, treatment of CD4+ T cells from GBS patients with IL-35 upregulated IL-35, STAT5 and STAT6 protein and T-bet, GATA3, Foxp3, IFN-γ, IL-4, IL-17A and TGF-β1 mRNA while inhibited levels of STAT3 and STAT4 protein and RORγt and IL-17A mRNA. These results indicate that IL-35 might play a potential role in GBS pathogenesis. Further studies are required in order to evaluate its role in GBS.

In autism spectrum disorders (ASD) many individuals have co-morbid immune dysregulation that can lead to inflammation in the brain and periphery. The novel cytokine interleukin (IL)-35 has described anti-inflammatory properties; however, the plasma levels of IL-35 in children with ASD have never been investigated. The plasma levels of IL-35 were measured by an enzyme-linked immunosorbent assay in 30 children with ASD and 39 typically developing (TD) controls. In the current study, we found that plasma IL-35 levels were significantly decreased in children with ASD compared with TD children. Furthermore, lower IL-35 levels were associated with worse behaviors as assessed using the aberrant behavior checklist. These findings are in line with other observations of decreased regulatory cytokines such as transforming growth factor beta and IL-10 in ASD, and associations with severity of behaviors. In conclusion, regulating the expression of IL-35 may provide a new possible target for the treatment of immune issues in ASD to address an imbalance between pro- and anti-inflammatory signals that alter the behavioral phenotype.

The balance between inflammatory and anti-inflammatory immune responses is maintained through immunoregulatory cell populations and immunosuppressive cytokines. Interleukin-35 (IL-35), an inhibitory cytokine that belongs to the IL-12 family, is capable of potently suppressing T cell proliferation and inducing IL-35-producing induced regulatory T cells (iTr35) to limit inflammatory responses. Over the past decade, a growing number of studies have indicated that IL-35 plays an important role in controlling immune-related disorders, including autoimmune diseases, infectious diseases, and cancer. In this review, we summarize the current knowledge about the biology of IL-35 and its contribution in different diseases, and we discuss the potential of and barriers to harnessing IL-35 as a clinical biomarker or immunotherapy. [ABSTRACT FROM AUTHOR]

• IL-35 release in clinical ARDS but reduced in non-survivor, suggesting anti-inflammatory potential of IL-35 in clinical ARDS. • Recombinant IL-35 treatment could improve survival in experimental ARDS. • Its protective effect is promoting differentiation of Helios+Foxp3+Tregs to improve uncontrolled inflammation in ARDS. • IL-35 could be a novel cytokine-targeted for the regulation of T cell differentiation in ARDS development. Regulatory T lymphocytes are important targets for the treatment of acute respiratory distress syndrome (ARDS). IL-35 is a newly identified IL-12 cytokine family member that plays an important protective role in a variety of immune system diseases by regulating Treg cell differentiation; however, the role of IL-35 in the pathogenesis of ARDS is still unclear. Here, we found that IL-35 was significantly elevated in adult patients with ARDS compared to controls. Additionally, IL-35 was positively and significantly correlated with IL-6, IL-10 and the oxygenation index (PaO2/FiO2 ratio) but negatively correlated with TNF-α, IL-1β and APACHE II score during ARDS. Moreover, the proportion of Treg/CD4+ cells in the peripheral blood of ARDS patients and the expression of NF-κB in PMBCs were significantly higher than in healthy individuals. Recombinant IL-35 improved survival in a murine model of CLP-induced ARDS. Additionally, IL-35 administration decreased the inflammatory response, as reflected by lower levels of cytokines (including IL-2, TNF-α, IL-1β and IL-6) and less lung damage in CLP-induced ARDS. Furthermore, recombinant IL-35 reduced the apoptosis of lung tissue and the expression of NF-κB signalling in a CLP-induced ARDS model and increased the proportion of Treg cells in spleen and peripheral blood. In vitro experiments revealed that IL-35 can affect the phosphorylation of STAT5 during differentiation of naïve CD4+ T lymphocytes into Foxp3+Helios+ Tregs. Our findings suggest that IL-35 attenuates ARDS by promoting the differentiation of naïve CD4+ T cells into Foxp3+Helios+ Tregs, thereby providing a novel tool for anti-ARDS therapy. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have proved that Th17 (T helper 17) cell subsets, a unique proinflammatory CD4+ T cell lineage, are deeply involved in the pathophysiology of allergic rhinitis (AR). IL-35, secreted mainly by natural Treg (nTreg) and depending on the expression of Foxp3, can effectively alleviate allergen-induced specific airway inflammation. However, the regulation of IL-35 in AR is not clear.Methods: Twenty AR children and 20 healthy controls were enrolled. The expression of serum IL-35 protein was detected and the correlation with Th17 cytokines (IL-17, IL-23, IL-27) expression was analyzed by enzyme-linked immunosorbent assay (ELISA). Peripheral blood mononuclear cells were prepared and stimulated by IL-35 to explore its effect on Th17 inflammation.Results: Serum IL-35 levels in AR were negatively correlated with serum IL-17 and IL-23 levels in AR. Recombinant IL-35 inhibits the Th17 response of PBMCs, which were mediated by the mitogen-activated protein kinase (MEK) and c-Jun N-terminal kinase (JNK) pathways.Conclusions: Our data demonstrate that IL-35 can inhibit Th17 response in AR through MEK and JNK pathways. [ABSTRACT FROM AUTHOR]

• IL-35 increased following L. infantum and L. donovani infection, in contrast to L. major and L. tropica. • Leishmania species up-regulate different groups of cytokines and modulate NO release in a different way. • Live parasites data might provide new insights into the mechanisms controlling Leishmania infections. Data on cellular immunity mediators in the early phase of human leishmaniasis are still limited and controversial. In order to mimic the changes of humoral mediators during the early phase of human natural infection, some Th1, Th2, Treg, and Breg cytokines, MCP-1, and the nitric oxide (NO) from human PBMC, stimulated by Leishmania infantum, Leishmania major, Leishmania donovani and Leishmania tropica infective metacyclic promastigotes, were determined. After 4 h of L. major, L. donovani, and L. tropica challenge, TNFα, IL-1β, IL-6 levels were significantly higher than negative control cultures with saline (SF) instead of Leishmania promastigotes, unlike L. infantum- stimulated TNFα and L. major -stimulated IL-1β. We obtained higher levels of IL-4 and IL-10 cytokines after stimulation of human PBMCs by L. infantum and L. donovani, compared to those observed after the challenge of PBMCs by L. major and L. tropica. Regarding IL-35, such cytokine levels were significantly increased following infection with L. infantum and L. donovani , in contrast to L. major and L. tropica. Up to our knowledge, we are the first to study the effect of four different species of Leishmania on IL-35 levels in human cells. Our study highlights how several Leishmania species can up-regulate different groups of cytokines (Th1, Th2, Treg and Breg) and modulate NO release in a different way. This original aspect can be explained by different Leishmania cell products, such as LPG, obtained from different strains/species of live parasites. Our findings would contribute to the development of new therapeutics or vaccination strategies. [ABSTRACT FROM AUTHOR]

IL-35, a relatively newly discovered cytokine belonging to the larger IL-12 family, shows unique anti-inflammatory properties, believed to be associated with dedicated receptors and signaling pathways. IL-35 plays a pivotal role in the development and the function of both regulatory B (Bregs) and T cells (Tregs). In order to further its therapeutic potential, a dairy Lactococcus lactis strain was engineered to express murine IL-35 (LL-IL35), and this recombinant strain was applied to suppress collagen-induced arthritis (CIA). Oral administration of LL-IL35 effectively reduced the incidence and disease severity of CIA. When administered therapeutically, LL-IL35 abruptly halted CIA progression with no increase in disease severity by reducing neutrophil influx into the joints. LL-IL35 treatment reduced IFN-γ and IL-17 3.7- and 8.5-fold, respectively, and increased IL-10 production compared to diseased mice. Foxp3+ and Foxp3− CD39+ CD4+ T cells were previously shown to be the Tregs responsible for conferring protection against CIA. Inquiry into their induction revealed that both CCR6+ and CCR6− Foxp3+or− CD39+ CD4+ T cells act as the source of the IL-10 induced by LL-IL35. Thus, this study demonstrates the feasibility and benefits of engineered probiotics for treating autoimmune diseases.

Abstract Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome with uncontrolled inflammation that is a central issue. Its main characteristic is inflammatory mediators and cytokines as well as agglutinating chemokines that injure target cells. Interleukin (IL)-35 is a newly identified IL-12 cytokine family member with structural similarities to other IL-12, IL-23, and IL-27 cytokines but unique immunological functions. How IL-35 functions in ARDS is unclear. The purpose of our study was to determine what role IL-35 played in the development of ARDS. Here we found serum IL-35 concentrations were significantly elevated in patients with ARDS relative to healthy people. Moreover, we established a mouse model of lipopolysaccharide- and cecal ligation and puncture-induced ARDS treated with neutralizing antibodies (anti-IL-35 Ebi3 or anti-IL-35 P35); the results showed that lung injury occurred more often than in untreated models and the inflammatory cytokines CXCL-1, tumor necrosis factor alpha, IL-6, and IL-17A increased significantly after neutralizing antibody treatment in bronchoalveolar lavage fluid and serum. Therefore IL-35 can protect against the development of ARDS. Even more interesting in our study was that we discovered IL-35 expression differed between lung and spleen across different ARDS models, which further demonstrated that the spleen likely has an important role in extrapulmonary ARDS model only, improving the ratio of CD4+/CD4+CD25+Foxp3+(Tregs). Meanwhile in our clinical work, we also found that the concentration of IL-35 and the ratio of CD4+/Treg in the serum are higher and the mortality is lower than those with the spleen deficiency in patients with extrapulmonary ARDS. Therefore, IL-35 is protective in ARDS by promoting the ratio of splenic CD4+/Tregs in extrapulmonary ARDS, and as such, may be a therapeutic target. Highlights • IL-35was protective against the development of ARDS. • In the CLP and LPS-induced ARDS model (splenectomized and non splenectomized groups), we found that spleen was not involved in IL-35 secretion in pulmonary ARDS but had a role in extrapulmonary ARDS. • IL-35 could promote the ratio of splenic CD4+/CD4+CD25+Foxp3+(Tregs) in extrapulmonary ARDS only, but not in pulmonary ARDS. [ABSTRACT FROM AUTHOR]

IL-35, a relatively newly discovered cytokine belonging to the larger IL-12 family, shows unique anti-inflammatory properties, believed to be associated with dedicated receptors and signaling pathways. IL-35 plays a pivotal role in the development and the function of both regulatory B (Bregs) and T cells (Tregs). In order to further its therapeutic potential, a dairy Lactococcus lactis strain was engineered to express murine IL-35 (LL-IL35), and this recombinant strain was applied to suppress collagen-induced arthritis (CIA). Oral administration of LL-IL35 effectively reduced the incidence and disease severity of CIA. When administered therapeutically, LL-IL35 abruptly halted CIA progression with no increase in disease severity by reducing neutrophil influx into the joints. LL-IL35 treatment reduced IFN-γ and IL-17 3.7- and 8.5-fold, respectively, and increased IL-10 production compared to diseased mice. Foxp3+ and Foxp3− CD39+ CD4+ T cells were previously shown to be the Tregs responsible for conferring protection against CIA. Inquiry into their induction revealed that both CCR6+ and CCR6− Foxp3+or− CD39+ CD4+ T cells act as the source of the IL-10 induced by LL-IL35. Thus, this study demonstrates the feasibility and benefits of engineered probiotics for treating autoimmune diseases. [ABSTRACT FROM AUTHOR]

Objective: IL‐35 is a newly discovered immunoregulatory cytokine that possesses the ability to inhibit CD4 + effector T cells and alleviate autoimmune diseases. The objective of this study was to investigate IL‐35 levels in patients with primary Sjogren's syndrome (pSS) and explore the roles of IL‐35 in the pathogenesis of pSS. Methods: Thirty‐four hospitalized patients with pSS were recruited, and 34 volunteers were enrolled as healthy controls. An ELISA was adopted to measure plasma IL‐35 levels. The levels of P35 and EBI3 mRNAs in peripheral blood mononuclear cells (PBMCs) were determined using real‐time quantitative PCR. The percentage of CD4 + EBI3 + T cells and CD19 + EBI3 + B cells was analysed using flow cytometry. Correlations between IL‐35 levels, P35 and EBI3 mRNAs, numbers of CD4 + EBI3 + T cells, CD19 + EBI3 + B cells and clinical parameters were analysed. Results: Significantly lower plasma IL‐35 levels, P35 and EBI3 mRNA levels, and percentages of CD4 + EBI3 + T cells but increased percentages of CD19 + EBI3 + B cells were observed in patients with pSS than in healthy controls. IL‐35 levels, EBI3 mRNA expression and the percentage of CD4 + EBI3 + T cells exhibited negative correlations with the ESSDAI score, whereas levels of the IL‐35 protein and EBI3 mRNA were negatively correlated with the ESR. Patients who were positive for anti‐SSB antibodies presented with lower IL‐35 levels and percentages of CD4 + EBI3 + T cells. Conclusions: Based on these results, a decrease in the IL‐35 levels may play an important role in the pathogenesis of pSS. IL‐35 may act as a potential therapeutic agent against inflammation in patients with pSS. [ABSTRACT FROM AUTHOR]

Interleukin 35 (IL-35) is the recently identified member of the IL-12 family of cytokines and provides the possibility to be a target for new therapies for autoimmune, inflammatory diseases. It is composed of an α chain (p35) and a β chain (EBI3). IL-35 mediates signaling by binding to its receptors, activates subsequent signaling pathways, and therefore, regulates the differentiation, function of T, B cells, macrophages, dendritic cells. Recent findings have shown abnormal expression of IL-35 in inflammatory autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes, psoriasis, multiple sclerosis, autoimmune hepatitis, experimental autoimmune uveitis. In addition, functional analysis suggested that IL-35 is critical in the onset and development of these diseases. Therefore, the present study will systematically review what had been occurred regarding IL-35 in inflammatory autoimmune disease. The information collected will help to understand the biologic role of IL-35 in immune cells, and give information about the therapeutic potential of IL-35 in these diseases. [ABSTRACT FROM AUTHOR]

Pathogenesis of thrombocytopenia is heterogeneous and resistance to treatment is a great challenge. In this study, we reviewed the demographic features of thrombocytopenic Egyptian patients. We also analyzed the role of T cell in chronic immune cases. IL-12, IL-35, IL-17, and TGF-β were measured by ELISA. The median age at the time of diagnosis was 30 years and its range was 14-70. The median platelet count at the time of diagnosis was 15 × 109/L. Regarding treatment and follow-up, there was an indication for treatment in 96% of patients. Of the 150 ITP patients who were given first-line therapy (corticosteroid 1 mg/kg/day PO), there was a complete response (CR) in 40.3% while 59.7% patients were nonresponsive to therapy. Forty-five chronic cases fulfilled the criteria for cytokine assay. Comparison between the case group and the control group revealed statistically significant lower platelet count in cases, while the four measured cytokines were statistically significant higher in cases rather than the control. Correlation between the platelet count and the level of cytokines was statistically insignificant. The remission rate in ITP on steroid as first-line therapy is less than 50%. The higher expression of IL-12 and IL-35in chronic ITP is due to the persistently higher Th1 activity which explains the continuity of the disease, while the higher expression of Treg cytokines (IL-17 and TGF-β) may be explained by effect of immunosuppression or upregulation of the receptors on Treg cells. [ABSTRACT FROM AUTHOR]

In autism spectrum disorders (ASD) many individuals have co-morbid immune dysregulation that can lead to inflammation in the brain and periphery. The novel cytokine interleukin (IL)-35 has described anti-inflammatory properties; however, the plasma levels of IL-35 in children with ASD have never been investigated. The plasma levels of IL-35 were measured by an enzyme-linked immunosorbent assay in 30 children with ASD and 39 typically developing (TD) controls. In the current study, we found that plasma IL-35 levels were significantly decreased in children with ASD compared with TD children. Furthermore, lower IL-35 levels were associated with worse behaviors as assessed using the aberrant behavior checklist. These findings are in line with other observations of decreased regulatory cytokines such as transforming growth factor beta and IL-10 in ASD, and associations with severity of behaviors. In conclusion, regulating the expression of IL-35 may provide a new possible target for the treatment of immune issues in ASD to address an imbalance between pro- and anti-inflammatory signals that alter the behavioral phenotype.

Abstract: Background: Regulatory T cells (Treg) play an important role in maintenance of homeostasis in vivo. Treg application to alleviate allo‐organ rejection is being studied extensively. However, natural Treg (nTreg) expansion in vitro is laborious and expensive. Antigen‐specific Treg are more effective and require lower cell numbers than use of nTreg for immune control. The baboon, as a non‐human primate experimental animal model, is widely used in xenotransplantation research. An effective method to generate baboon xeno‐specific Treg would benefit research on immune tolerance in xenotransplantation using this model system. Method: Baboon tolerogenic dendritic cells (tolDC) were generated in 3 days from monocytes isolated from baboon peripheral blood mononuclear cells in medium supplemented with anti‐inflammatory cytokines. After loading with porcine‐specific (PS) in vitro‐transcribed RNA (ivtRNA), tolDC were used to induce CD4+ T cells to become porcine‐specific Treg (PSTreg) in cocultures supplemented with IL‐2 and rapamycin for 10 days. Anti‐inflammatory and inflammatory cytokine expression was evaluated at the mRNA and protein levels in both baboon tolDC and PSTreg. Functional assays, suppression of activation markers on porcine‐specific effector T cells (PSTeff) and inhibition of PSTeff proliferation, were used to test PSTreg specificity. Results: TolDC generated with this method exhibited a tolerogenic phenotype, expressed CCR7 and produced high levels of IL‐10 and TGF‐β1, whereas IL‐12p40 and IFN‐γ were not expressed. PSTreg were successfully generated in cocultures of CD4+ T cells and PS ivtRNA‐loaded tolDC. They exhibited a CD3+ CD4+ CD25+ CD127low/− CD45RAlow Foxp3+ phenotype and were characterized by high expression of IL‐10 and TGF‐β1 mRNA and protein. They showed upregulated expression of EBI3 and GARP mRNA. PSTreg exhibited highly suppressive effects toward PSTeff, secreting high amounts of IL‐10 and TGF‐β1 cytokine upon interaction with PSTeff and suppressing IFN‐γ expression on PSTeff. Conclusion: In this study, a fast 3‐day method to generate baboon‐derived tolDC is provided that allows subsequent induction of PSTreg displaying high porcine‐antigen specificity and expression of IL‐10 and TGF‐β1. Porcine‐specific baboon Treg can be used in porcine solid organ or cell xenotransplantation studies through adoptive cell transfer into host baboons. [ABSTRACT FROM AUTHOR]

Background: Interleukin (IL)-35 is a novel inhibitory cytokine and has recently been implicated in tumor immunity. However, the role of IL-35 in prostate cancer (PCa) has not been elucidated. Objective: To evaluate the role of plasma IL-35 in the diagnosis and prognosis of PCa in Chinese patients undergoing initial prostate biopsy. Materials and methods: Using ELISA, plasma IL-35 levels were measured in 180 patients, who underwent a prostate biopsy. The clinical correlation of IL-35 with clinicopathological parameters was also evaluated. Univariate and multivariate logistic regression and receiver operating characteristic (ROC) curve analysis were performed to establish the role of IL-35 as a clinical biomarker. Results: Seventy-five (41.6%) of patients were histopathologically confirmed to have PCa. Plasma IL-35 levels were significantly higher in PCa patients (134.48±78.48 pg/mL) compared to non-PCa patients (67.22±24.08 pg/mL). ROC analysis showed that IL-35 was an independent predictor of PCa. Furthermore, IL-35 was found to be a significantly independent predictor of PCa in a group of patients with prostate-specific antigen levels between 4 and 10 ng/mL; was also able to predict advanced PCa from localized PCa and bone metastasis positive PCa from negative PCa. Conclusion: Our data suggest for the first time that plasma IL-35 levels are correlated with PCa and is the independent predictor of PCa progression and metastasis. Thus, IL-35 could be utilized as a potential biomarker for diagnosis and prognosis of PCa, could also aid in decision making and predict the stage of the disease. [ABSTRACT FROM AUTHOR]

Asthma is a chronic airway inflammation that is characterized by intense eosinophil infiltrates, mucus hypersecretion, airway remodeling, and airway hyperresponsiveness. Interleukin (IL)-35 and IL-37 are two cytokines with anti-inflammatory effects found in immune response. Recent findings suggested that expressions of IL-35 and IL-37 are abnormal in asthma. Functional analysis further confirmed the important roles of them in the pathogenesis of asthma. The present study reviewed the updated evidence indicating the roles of IL-35 and IL-37 in asthma. Hopefully, the information obtained may lead to a better understanding of the pathogenesis of the disease. [ABSTRACT FROM AUTHOR]

The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they comprise two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than six cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein-Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses, such as helper T (Th)1, Th2, and Th17, to anti-inflammatory responses, such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells, such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus, promiscuity within the IL-6/IL-12 family cytokines complicates structural and functional clarification and assignment of individual cytokines. A better understanding of the recent advances and expanding diversity in molecular structures and functions of the IL-6/IL-12 family cytokines could allow the creation of novel therapeutic strategies by using them as tools and targeted molecules. [ABSTRACT FROM AUTHOR]

Introduction Previous studies have shown that some cytokines mediate the effect of IGF-1 on inflammation and also association between IGF-1 and vascular endothelial dysfunction. Due to the discrepancies in the inflammatory and anti-inflammatory roles of IL-27 and IL-35, the effects of these cytokines and their IGF-1-mediating role were investigated regarding chronic joint inflammation and synovial blood flow. Method Male rats were divided into two main groups of histopathology (n = 80) and blood flow (n = 72). These were further divided into ten subgroups of control, vehicle, IGF-1, IL-27, IL-35, their antagonists, IGF-1 + IL-27 antagonist, and IGF-1 + IL-35 antagonist. Inflammation was induced by intra-articular injection of complete Freund adjuvant. Two weeks later (in order to induce chronic inflammation), vehicle or drugs were injected into the joint space every other day until day 28, on which inflammatory indices were assessed histopathologically. In the second subgroups, vehicle or drugs were administered by super-fusion on day 28 and their effects on the joint blood flow (JBF, laser Doppler perfusion method) and the systemic blood pressure were assessed. Results Endogenous IL-27 and IL-35 had inflammatory roles and IGF-1 had no effect. IL-27 and IL-35 antagonists had the highest anti-inflammatory and anti-angiogenesis effects and these effects were inhibited by IGF-1. Total inflammation score was 4.5 ± 0.42, 3.50 ± 0.5, 2.25 ± 0.45 and 1.50 ± 0.42 for vehicle, IGF-1 antagonist, IL-27 antagonist and IL-35 antagonist respectively. A significant increase was induced in JBF by IGF-1 antagonist and combination of IGF-1 + IL-35 antagonist. Conclusion IL-27 and IL-35 antagonists may be suitable goals for the treatment of chronic joint inflammation while their anti-inflammatory effects are not exerted via the changes in JBF. [ABSTRACT FROM AUTHOR]

Postinfluenza pneumococcal pneumonia is an important cause of global morbidity and mortality. What causes this increased susceptibility is not well elucidated. IL-35 is a newly described cytokine in infectious tolerance. A murine model was established to study postinfluenza pneumococcal pneumonia and evaluate the role of IL-35 in host defense against postinfluenza pneumococcal pneumonia. Pulmonary IL-35 was rapidly up-regulated during murine influenza infection, which was partially mediated by type I IFN-α/β receptor signaling pathway. Secondary pneumococcal infection led to a synergistic IL-35 response in influenza-infected mice. Clinical analysis showed that IL-35 levels were significantly elevated in the patients with influenza infection compared with healthy individuals and influenza infection could induce IL-35 production from human peripheral blood mononuclear cells. These data suggest that IL-35 contributes to the increased susceptibility to secondary pneumococcal pneumonia at least in part by inhibiting the early immune response. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is the most common hematological malignancy in adults, but the etiology of it remains poorly understood. IL-35 is a recently described cytokine composed of an IL-12 subunit p35 and an IL-27 subunit Epstein–Barr virus induced gene 3 (EBI3), and has an immunosuppressive effect on inflammation through induction of regulatory T cells (Tregs) and suppression of Th1 and Th17. Recently, we have illustrated that concentrations of IL-35 in peripheral blood are up-regulated in newly diagnosed (ND) AML patients. However, whether IL-35 in bone marrow is increased in AML patients is not clear. In this study, we examined IL-35 in bone marrow by various methods including RT-PCR, ELISA, FCM and IHC, and found that IL-35 levels are also increased significantly in bone marrow of adult AML patients. Furthermore, we investigated that concentrations of bone marrow IL-35 in ND group were higher than that in complete remission (CR) group and control group, but there was no significant difference compared to that in relapse group. In conclusion, IL-35 was elevated in bone marrow of adult AML patients and this increase was correlated with the clinical stages of malignancy, suggesting that IL-35 is involved in pathogenesis of AML. [ABSTRACT FROM AUTHOR]

Objective. IL-35 is the most recently identified member of the IL-12 family. It consists of EBV-induced gene 3 (EBI3) and IL-12α chain p35. We investigated whether IL-35 enhances the in vitro immunosup-pressive function of peripheral blood isolated from patients with RA. Methods. Peripheral blood was harvested from 17 active and 10 inactive RA patients and IL-35 concentrations were quantified using an ELISA. An expression vector containing IL-35 with a FLAG tag at the carboxyl-terminus was constructed by covalently linking EBI3 and IL-12α (p35). The function of IL-35 was then evaluated in a suppression assay using T cells isolated from human RA patients with CD2, CD3 and CD28 antibodies. Results. Serum IL-35 levels and the number of Treg were decreased significantly in patients with active RA. There was a significant correlation between serum IL-35 and the 28-joint DAS with ESR (DAS28-ESR) in patients with active RA. IL-35 treatment enhanced the regulatory function, suppressing the levels of inflammatory cytokines such as IL-17 and IFN-γ and the cellular growth of effector T cells stimulated by conjugation with CD2, CD3 and CD28. Conclusion. These data revealed that IL-35 might suppress T cell activation during the peripheral immune responses of RA. Therefore our data suggest that IL-35 might have multiple therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Interleukin (IL) 35 was recently identified as an additional anti-inflammatory and immunosuppressive cytokine. However, the role of IL-35 in allergic rhinitis is not well understood. The effect of IL-35 on other cytokines in allergic responses is also unclear. Objective: To investigate, in mice with allergic rhinitis, the effect of IL-35 on other cytokines associated with allergic rhinitis. Methods: A murine model of allergic rhinitis was established, and splenic cells were collected. Ovalbumin-specific allergic T-cell response was measured. The production of cytokines (T helper 1 interferon-gamma), Th2 (IL-4, IL-5, IL-13), Th17 (IL-17), IL-12 family (IL-12, IL-23, IL-27), IL-2, tumor necrosis factor-alpha, transforming growth factor-beta, and IL-10) stimulated with antigen was also measured in the presence or absence of IL-35. Results: IL-35 significantly inhibited the ovalbumin-specific T-cell response. It also significantly reduced the production of IL-4, IL-5, IL-13, IL-17, IL-23, and TNF-alpha, and significantly increased the production of IL-2, IL-10, and IL-27. Conclusion: This study showed that IL-35 inhibits allergic T-cell response and has the ability to modulate the production of IL-2, IL-4, IL-5, IL-10, IL-13, IL-17, IL-23, IL-27, and TNF-alpha in mice with allergic rhinitis. This study also indicated the possibility of a novel therapy with IL-35 for the control of allergic rhinitis. [ABSTRACT FROM AUTHOR]

We investigated the plasma concentration of the novel regulatory cytokine IL-35 and intracytosolic pattern recognition receptors nucleotide-binding oligomerization domain (NOD)-like receptors in granulocytes and explored their potential implication in disease severity monitoring of allergic asthma. The expression of circulating IL-35 and other pro-inflammatory mediators in asthmatic patients or control subjects were evaluated using enzyme-linked immunosorbent assay (ELISA). The intracellular expressions of NOD1 and NOD2 in CCR3+ granulocytes were assessed using flow cytometry. Plasma concentrations of IL-35, IL-17A, basophil activation marker basogranulin, and eosinophilic airway inflammation biomarker periostin were significantly elevated in allergic asthmatic patients compared to non-atopic control subjects (all probability ( p) <0.05). Both granulocyte markers exhibited significant and positive correlation with plasma IL-35 concentration in asthmatic patients (all p < 0.05). Significant positive correlation was also identified between plasma concentrations of IL-35 and periostin with disease severity score in asthmatic patients (both p < 0.05). The basophil activation allergenicity test was positive in allergic asthmatic patients but not in control subjects. Despite significantly elevated eosinophil count in allergic asthmatic patients, downregulation of NOD2 in CCR3+ granulocytes was observed in these patients (both p < 0.05). A negative correlation between plasma concentrations of tumor necrosis factor family member LIGHT and soluble herpesvirus entry mediator was observed in patients with elevated plasma concentration of IL-35 ( p < 0.05). Aberrant expression of NOD2 in granulocytes may be contributed to the impaired innate immunity predisposing allergic asthma. IL-35 may serve as a potential surrogate biomarker for disease severity of allergic asthma. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-12 family cytokines are heterodimers of an α-chain (p19, p28 and p35) and a β-chain (p40 and Ebi3), present as IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/Ebi3) and IL-35 (p35/Ebi3), and play key roles in immune responses in mammals. One p35 and up to three p40 genes have been cloned in some fish species. The identification of three active p35 genes, along with three p40 paralogues in salmonids in the current study further expands the repertoire of IL-12, IL-23 and IL-35 molecules in these species. The multiple p35 genes in teleost fish appear to have arisen via whole genome duplications. The different paralogues of the subunits are divergent, and differentially expressed and modulated by PAMPs and proinflammatory cytokines, hinting that distinct isoforms could be produced in response to infection. Therefore, the expanded IL-12 cytokine family may provide an unprecedented level of regulation to fine tune the immune response in fish. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. It is believed to be caused by exposure to pathogenic antigens in genetically susceptible individuals but the causative antigen has not been identified. The formation of non-caseating granulomas at sites of ongoing inflammation is the key feature of the disease. Other aspects of the pathogenesis are peripheral T-cell anergy and disease progression to fibrosis. ManyTcell- associated cytokines have been implicated in the immunopathogenesis of sarcoidosis, but it is becoming apparent that IL-12 cytokine family members including IL-12, IL-23, IL- 27, and IL-35 are also involved. Although the members of this unique cytokine family are heterodimers of similar subunits, their biological functions are very diverse. Whilst IL-23 and IL-12 are pro-inflammatory regulators of Th1 andTh17 responses, IL-27 is bidirectional for inflammation and the most recent family member IL-35 is inhibitory. This review will discuss the current understanding of etiology and immunopathogenesis of sarcoidosis with a specific focus on the bidirectional impact of IL-12 family cytokines on the pathogenesis of sarcoidosis. [ABSTRACT FROM AUTHOR]

Objective To investigate expression of the Th17 cells and Treg cells in breast cancer tumor and related cytokines in the peripheral blood, and study its relationship with lymphatic metastasis. Methods Flow cytometry was applied to test Th17 cells and Treg cells in the peripheral blood of both 35 cases of breast cancer and 20 controls. ELASA method was used to test the expression cytokines of IL-23, IL-10, IL-35 and TGF-β. Results The frequency of Th17 cells and Treg cells in breast cancer was significantly higher that in healthy volunteers ( P < 0.05) . The frequency of Th17 cells and Treg cells in patients of lymphatic metastasis was significantly higher that in patients of non-lymphatic metastasis ( P < 0.05), then Treg cells increased more obviously than Th17 cells. The radio of Th17/Treg cells in patients of lymphatic metastasis was significantly lower than in patients of non-lymphatic metastasis (P<0.05) .IL-23, IL-10 and TGF-β expression levels were higher than those in healthy control group (P<0.05), but IL-35 expression levels were lower. There was no significant difference in IL-23 expression between lymphatic metastasis group and non-lymphatic metastasis group (P> 0.05), while there were significant differences in expression of IL-10, TGF-β and IL-35 between two groups (P< 0.05) .Conclusions The trend of changes in the related cytokines IL-23, IL-10 and TGF- (3 is in agreement with that of Th17 cells and Treg cells in the peripheral blood of breast cancer. The rise of IL-35 and Treg cells shows a negative correlation. The imbalance of Th17/Treg may be one of the factors leading to tumour progression. [ABSTRACT FROM AUTHOR]

Résumé: Le développement de technologies innovantes permet l’identification et la caractérisation régulière de nombreuses molécules. C’est ainsi qu’un certain nombre d’interleukines a pu être identifié et caractérisé ces dernières années. Nous détaillons dans cet article les caractéristiques structurales et fonctionnelles des interleukines IL-34 à IL-38 et en particulier leur rôle dans les rhumatismes inflammatoires. L’IL-34 a principalement une fonction de stimulation et de prolifération des ostéoclastes et intervient donc directement dans la destruction osseuse au cours de la polyarthrite rhumatoïde. L’IL-35 est exprimée par les cellules T régulatrices et à ce titre possède une action anti-inflammatoire en restaurant les capacités suppressives de ces cellules et en inhibant la voie TH17. L’IL-37 a pour sa part une action anti-inflammatoire en exerçant un rétro-contrôle sur la sécrétion des cytokines pro-inflammatoires. L’IL-36 fait partie de la famille de l’IL-1 et est présente sous trois formes différentes. Elle a principalement été étudiée dans le psoriasis et le rhumatisme psoriasique, mais son rôle pro-inflammatoire s’exerce aussi dans la polyarthrite rhumatoïde. L’antagoniste spécifique de l’IL-36, l’IL-36Ra se fixe sur son récepteur et empêche la transduction du signal. L’IL-38 a été identifiée récemment et aurait une action proche de l’IL-36Ra puisqu’elle se fixe sur le récepteur del’IL-36 et inhibe son action en particulier la réponse TH17. Si les fonctions exactes de ces différentes cytokines demandent encore à être précisées, l’amélioration de nos connaissances des mécanismes de régulation d’un phénomène inflammatoire chronique comme la polyarthrite rhumatoïde, peut permettre le développement de nouvelles cibles thérapeutiques. [ABSTRACT FROM AUTHOR]

Abstract: Interleukin (IL)-35 is a novel heterodimeric cytokine in the IL-12 family and is composed of two subunits: Epstein-Barr virus-induced gene 3 (EBI3) and IL-12p35. IL-35 is expressed in T regulatory (Treg) cells and contributes to the immune suppression function of these cells. In contrast, we found that both IL-35 subunits were expressed concurrently in most human cancer cell lines compared to normal cell lines. In addition, we found that TNF-α and IFN-γ stimulation led to increased IL-35 expression in human cancer cells. Furthermore, over-expression of IL-35 in human cancer cells suppressed cell growth in vitro, induced cell cycle arrest at the G1 phase, and mediated robust apoptosis induced by serum starvation, TNF-α, and IFN-γ stimulation through the up-regulation of Fas and concurrent down-regulation of cyclin D1, survivin, and Bcl-2 expression. In conclusion, our results reveal a novel functional role for IL-35 in suppressing cancer activity, inhibiting cancer cell growth, and increasing the apoptosis sensitivity of human cancer cells through the regulation of genes related to the cell cycle and apoptosis. Thus, this research provides new insights into IL-35 function and presents a possible target for the development of novel cancer therapies. [Copyright &y& Elsevier]

Abstract: The heterodimeric IL-12 cytokine family is characterized by the sharing of three α (p19, p28, p35) and two β (p40 and Ebi3) subunits, and includes IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/Ebi3) and IL-35 (p35/Ebi3). In this study, the dimerization interfaces of IL-12 family members were characterized, with emphasis on IL-35. Ebi3 and p35 subunits from human and mouse paired effectively with each other, indicating there is no species barrier to IL-35 dimerization and suggesting a conserved dimerization interface. Specific p35 residues that contribute to formation of the IL-12 interface were assessed for their contribution to the IL-35 interface, and candidate Ebi3 residues were screened for their contribution to both IL-27 and IL-35 interfaces. Several residues were identified as critical to the IL-12 or IL-27 interfaces. Conversely, no single mutation was identified that completely disrupts p35/Ebi3 pairing. Linear alanine scanning mutagenesis on both p35 and Ebi3 subunits was performed, focusing on residues that are conserved between the mouse and human proteins. Additionally, a structure-based alanine-scanning approach in which mutations were clustered based on proximitiy was performed on the p35 subunit. Both approaches suggest that IL-35 has distinct criteria for subunit pairing and is remarkabley less sensitive to structural perturbation than IL-12 and IL-27. Additionally, studies using a panel of anti-p35 and anti-Ebi3 antibodies indicate differential availability of epitopes within IL-12 family members that share these subunits, suggesting that IL-35 has distinct structural features, relative to IL-12 and IL-27. These results may be useful in future directed therapeutic targeting of IL-12 family members. [Copyright &y& Elsevier]

Production of cytokines by immune cells in response to stimuli and the binding of cytokines to specific receptors on target cells is a central feature of the immune response. The IL-12 cytokine family is particularly influential in determining the fate of T cells and is characterized by the sharing of cytokine and receptor subunits. A thorough understanding of the molecular interactions within this family will be a key to the development of therapeutic inhibitors or enhancers of IL-12 family function. While the current structural and molecular data for IL-12 family members is limited, there is ample information on the structurally related IL-6 cytokine family. This review will summarize the current structural and mutagenesis data within the IL-12 family and will attempt to utilize similarities between the IL-6 and IL-12 families to understand molecular interactions between IL-12 family subunits and with receptor components. [ABSTRACT FROM AUTHOR]

Abstract: Epstein–Barr virus-induced gene 3 (Ebi3) and the p35 subunit of IL-12 have been reported to form a heterodimeric cytokine, named IL-35, in human and mouse. In mice, IL-35 has been shown to be constitutively expressed by CD4+CD25+Foxp3+ regulatory T cells (Tregs) and suggested to contribute to their suppressive activity. However, human CD4+CD25+Foxp3+ Tregs do not constitutively express detectable amounts of IL-35 in both mRNA and protein levels. Circulating CD4+CD25+ Treg frequency of chronic Hepatitis B patients significantly correlates with serum viral load. In this study, we investigated whether IL-35 expression could be detected in CD4+ T cells from peripheral blood of chronic Hepatitis B patients. Using both RT-PCR and immunoprecipitation plus Western blot analysis, we demonstrated that IL-35 expression could be detected in the CD4+ T cells from peripheral blood of Chronic Hepatitis B patients. [Copyright &y& Elsevier]

Advances in cytokine biology have helped us understand the complex communication that takes place between antigen-presenting cells and cells of the adaptive immune system, such as T cells, which collectively mediate an appropriate immune response to a plethora of pathogens while maintaining tolerance to self-antigens. The interleukin-12 (IL-12) cytokine family remains one of the most important and includes IL-12, IL-23, IL-27, and the recently identified IL-35. All four are heterodimeric cytokines, composed of an α chain (p19, p28, or p35) and a β chain (p40 or Ebi3), and signal through unique pairings of five receptor chains (IL-12Rβ1, IL-12Rβ2, IL-23R, gp130, and WSX-1). Despite the interrelationship between the cytokines themselves and their receptors, their source, activity, and kinetics of expression are quite different. Studies using genetically deficient mice have greatly enhanced our understanding of the biology of these cytokines. However, interpretation of these data has been complicated by the recent realization that p40−/−, p35−/−, and Ebi3−/− mice all lack more than one cytokine (IL-12/IL-23, IL-12/IL-35, and IL-27/IL-35, respectively). In this review, we compare and contrast the biology of this expanded IL-12 family and re-evaluate data derived from the analysis of these dual cytokine-deficient mice. We also discuss how the opposing characteristics of the IL-12 family siblings may help to promote a balanced immune response. [ABSTRACT FROM AUTHOR]

It is well known that RA (Rheumatoid arthritis) is an autoimmune disease characterized by multiple and symmetric arthropathy. The main pathological features of RA are synovial hyperplasia, angiogenesis, pannus formation, inflammatory cell infiltration, articular cartilage, bone destruction, and ultimately joint dysfunction, even deformity. IL-35 (Interleukin-35) is a new member of the IL-12 (Interleukin-12) family, which is an immunosuppressive and anti-inflammatory cytokine secreted mainly by Treg (T regulatory cells). There is evidence suggested that IL-35 can attenuate the progression of RA through influencing the immune and pathological process. It suggests that IL-35 played an important role in the pathogenesis of RA, and can be used as a potential target for the future treatment of RA. This review summarizes the recent advances of IL-35 in the pathological roles and the therapeutic potential roles in RA. [ABSTRACT FROM AUTHOR]