Recently, new complexities in cell fate decision for helper T cells have emerged. induces differentiation of na?ve CD4+ T cells to become regulatory T cells (Tregs). Th17 cells are now known to play an important role not only in the pathogenesis of inflammation and autoimmune diseases, but also host defense against extracellular bacteria. Conversely, extensive data substantiate the role of Tregs as essential in maintenance of peripheral tolerance. Selectively targeting Tregs and Th17 cells are likely to be important strategies in the treatment of inflammatory and autoimmune diseases in humans. polymorphisms are associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) (12). IFN- also activates Stat1 which further induces T-bet to form an autocrine feedback loop for IFN- production (2). T-bet promotes not only IFN- production but also suppression of Th2 cytokines production by T cells (2). On the other hand, Th2 cells produce IL-4, IL-5, and IL-13 (1). IL-4 activates Stat6, which up-regulates the expression of GATA-binding protein 3 (GATA-3) (1). Th2 cytokines are potent activators of B-cell Immunoglobulin E production, eosinophil recruitment, and mucosal expulsion mechanisms, and are essential for promoting host defense against helminths and other parasites (1). In addition, Th2 cells have been shown to mediate allergic diseases such as asthma, rhinitis, and atopic dermatitis (11). Traditionally, autoimmune diseases had been assumed to be associated with dysregulated Th1 responses (13). Because the treatment with anti-IL-12p40 antibody was effective in Crohn’s disease (CD) and psoriasis (14, 15), it was further assumed that IL-12-mediated IFN- production and Th1 response were involved in the pathogenesis of autoimmunity. However, it was shown that IFN- deficiency exacerbated rather than ameliorated mouse models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) (16). Subsequently, a new cytokine, which consists of IL-23p19 and IL-12p40, was identified and termed IL-23 (17). Interestingly, Rabbit Polyclonal to C-RAF (phospho-Thr269) the IL-23 receptor (IL-23R) forms dimers with the IL-12R1 chain shared by IL-12 and IL-23 (18). IL-23R is predominantly expressed on T and natural killer (NK) cells (18, 19). IL-23 activates Janus kinase 2 (Jak2) and tyrosine kinase 2 (Tyk2), which in turn leads to activation of Stat1, Stat3, Stat4, and Stat5, among which Stat3 is the predominant factor phosphorylated by this cytokine (17, 18). Of note, IL-23p19-deficient mice or IL-12p40-deficient (IL-12/IL-23-deficient) mice were resistant to collagen-induced arthritis (CIA) and EAE (20, 21). However, IL-12p35-deficient mice had increased susceptibility to CIA and EAE (20, 21). These studies directly negated the pathogenic role of the IL-12/IFN- axis in autoimmunity. This was an important piece of information that led to the unraveling of the Th1/Th2 Lopinavir (ABT-378) IC50 paradigm as an explanation of autoimmunity. Accordingly, additional studies on IL-23p19-deficient mice and the anti-IL-23p19 antibody revealed that IL-23, but not IL-12, was the Lopinavir (ABT-378) IC50 culprit in autoimmunity, at least in mouse disease models (21-23). The pathogenic role of IL-23 was also confirmed by the phenotype of IL-23p19 transgenic mice, in which premature death, systemic inflammation, anemia, and elevated serum levels of inflammatory cytokines and acute phase proteins were observed Lopinavir (ABT-378) IC50 (22). In human disease, the mRNA levels of both IL-23p19 and IL-12p40 were shown to be increased in skin lesions of psoriatic patients (24), suggesting that elevated IL-23 contributed to the pathogenesis of psoriasis. Therefore, IL-23 began to attract attention as a factor crucial to inflammation and autoimmune diseases. The IL-23/IL17 axis in inflammation While it was becoming clear that IL-23 was the culprit in autoimmune and inflammatory diseases, the question remained, how was it acting? Another inflammatory cytokine, IL-17, was noted to be produced by activated purified T cells in the presence of LPS-stimulated dendritic cells (DCs) (5). It was also found that IL-23 promoted IL-17 production from memory T cells and this production was suppressed by treatment with anti-IL-12p40 antibody (5). Now IL-17 is recognized as the founding member of a family of proinflammatory cytokines: IL-17 (IL-17A), IL-17B, IL-17C, IL-17D, IL-17E (known as IL-25), and IL-17F (6). IL-17A and IL-17F induce the production of various proinflammatory cytokines such as tumor necrosis factor- (TNF- ), IL-1, and IL-6, and CXC chemokines from monocytes, airway.