IL-17 Family (Discovery, Structure, Resource, and Function) IL-17A (commonly referred to as IL-17) was first identified as a product of rodent activated T cells in 1993 and was initially known as cytotoxic T lymphocyte associated antigen 8 (CTLA-8) . Mouse monoclonal to CD8/CD38 (FITC/PE) blocking IL-17-mediated pathway is just Lesinurad sodium beginning, and more fully investigation and reflection are required. Taking together, targeting IL-17-mediated responses may open up new areas of potential clinical treatment for AILD. 1. Introduction Liver is an immunological organ with unique properties of immune tolerance, which can lead to systemic immune tolerance. Many genetically susceptible individuals suffer from autoimmune liver diseases (AILD) while some unidentified environmental factors trigger the breach in immune tolerance resulting liver as a victim. However, the exact pathogenesis of AILD is still unknown. Autoimmune hepatitis (AIH), main biliary cirrhosis (PBC), main sclerosing cholangitis (PSC), and autoimmune sclerosing cholangitis are the major forms of AILD. Besides, a proportion of patients within the spectrum of AILD may present with overlapping features of two classical Lesinurad sodium disorders such as AIH, PBC, and PSC. These patients are often referred to as overlap syndromes [1, 2]. AILD have fluctuating and progressive courses with alternating relapses and quiescences. The spectrum of AILD is usually diverse, ranging from insidious onset with abnormal liver function assessments to fulminant hepatic failure. The causes of these clinical conditions are complex and most likely heterogeneous. The mechanisms responsible for the progression of AILD are yet to be fully clarified. However, recent studies have exhibited that cytokines play a pivotal role in the induction of immune responses during the development and progression of liver diseases. Among them, IL-17 family is one of the dominant pathogenic components in autoimmune inflammatory diseases, such as multiple sclerosis (MS), psoriasis, and rheumatoid arthritis (RA) [3C5]. Of interest, its role in AILD still requires clarification. On this basis, this review addresses the current data regarding the functions of IL-17 signaling in the pathogenesis of AILD and provides new insight into therapeutic potential of targeting IL-17-mediated responses. 2. General Features of Interleukin-17 2.1. IL-17 Family (Discovery, Structure, Resource, and Function) IL-17A (generally referred to as IL-17) was first identified as a product of rodent activated T cells in 1993 and was initially known as cytotoxic T lymphocyte associated antigen 8 (CTLA-8) . Since then, other five users of IL-17 family, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F have been discovered based on homology in amino acid sequences [6C9]. IL-17A is the most well investigated member of the IL-17 family and functions on multiple cell types to enhance the production of various proinflammatory molecules including cytokines (such as TNF and IL-6), chemokines (such as CXCL2 and MCP-1), mucins acute phase proteins, and matrix metalloproteinases [10C16]. Overall, IL-17A exerts a wide range of functions in autoimmune diseases, host defense, transplantation, allergy, and malignancy [17C21]. With the family, IL-17F is the most homologous protein to IL-17A (~60%) and resembles IL-17A in both the cellular sources and regulation function . Interestingly, IL-17A and IL-17F exist as homodimers . In addition, IL-17A and IL-17F also form a heterodimeric cytokine (IL-17A/F) with intermediate signaling potency . Th17, a subset of CD4+T cells named for their ability to preferentially produce IL-17, is recognized as the major suppliers of IL-17A and IL-17F . In addition, several innate immune cell types are described as sources for IL-17, including and C/EBPto induce the transcription of inflammatory gene such as IL-6 . By contrast, IL-17R-Take action1-TRAF-NF-in human BECs for further recruit of LCsMouse models???IL-12Rand TGF-in Kupffer cells by IL-17 and in turn promotion of IL-17 expressing cells differentiation[68, 69] Open in a separate window AIH: autoimmune hepatitis; PBC: main biliary cirrhosis; BEC: biliary epithelial cells; MIP-3receptor II; PSC: main sclerosing cholangitis; TLR: Toll-like receptor; BDL: bile duct ligation; HSC; hepatic stellate cells; 2OA: 2-octynoic acid. 3.1. Autoimmune Hepatitis AIH is usually a chronic inflammatory liver condition of unknown etiology that is putatively initiated by the aberrant autoaggressive immunity against hepatocyte-specific autoantigens . AIH is usually a progressive necroinflammatory disease characterized by elevated Lesinurad sodium aminotransferase levels, hypergammaglobulinemia, circulating autoantibodies, and histological evidence of interface hepatitis.