Cytokines play critical roles in immune responses against various pathogens. Th1 cells with characteristic production of IFN-g are important for defense against intracellular pathogens while Th2 cells producing mainly IL-4 are essential for expulsion of extracellular pathogens. IL-12 and IL-4 induce the differentiation of Th1 and Th2 cells, respectively. Recently, two heterodimeric cytokines, IL-23 and IL-27, were identified, which have structural and functional homology to IL-12. IL-27, composed of p28 plus Epstein Barr Virus-induced gene (EBI)-3, is a member of the IL-12 cytokine family. IL-27 is produced early after activation of antigen-presenting cells. Stimulation of naïve CD4+ T cells with IL-27 through WSX-1 (IL-27Rα) initiates the differentiation of CD4+ T cells into Th1 populations. IL-27/WSX-1 thus is critical for proper induction of Th1 responses and lack of WSX-1 results in the impaired Th1 responses with reduced resistance against Leishmania major infection in mice. Recent studies revealed that L-27/WSX-1 signaling also has an anti-inflammatory property. In Trypanosoma cruzi infection, various pro-inflammatory cytokines including TNF-α and IL-6, and even IFN-γ, were over produced causing lethal inflammatory responses in WSX-1-/- mice. These data revealed that IL-27/WSX-1 has a suppressive role for pro-inflammatory cytokine production and that IL-27/WSX-1 may work to suppress and/or terminate immune responses and inflammation. IL-27/WSX-1 thus regulates immune responses and inflammation both positively and negatively. Molecular basis for these two-sided roles of IL-27/WSX-1 will be discussed.
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