The Double Identity of WSX-1 (IL-27R) as an Initiator and an Attenuator of Immune Responses

Two heterodimeric cytokines, IL-23 and IL-27, were recently 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 and induces proliferation of naïve CD4+ T cells upon antigen recognition. Stimulation of naïve CD4+ T cells with IL-27 through WSX-1, a subunit of functional IL-27 receptor complex, initiates the differentiation of CD4+ T cells into Th1 populations through induction of T-bet followed by expression of IL-12Rb2. IL-27 / WSX-1 thus is critical for proper induction of Th1 responses and lack of WSX-1 results in the impaired Th1 responses in mice. Recent studies revealed that L-27 / WSX-1 signaling also has an anti-inflammatory property. In some protozoan 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. Taken together, IL-27 / WSX-1 thus has double identity as an initiator and as an attenuator of immune responses and inflammation.