Abstract
<abstract> Tyrosine kinase 2 (Tyk2), which associates with the receptors for type I interferon (IFN) and interleukins (IL)-6, IL-10, IL-12, and IL-23, is critical to mediate cytokine-induced signals. Tyk2 plays an essential role in the constitutive production of small amount of type I IFNs and in the promotion of differentiation from naïve T cells into Th1 or Th17 effector cells via IL-12- and IL-23-induced signals. Additionally, Tyk2-mediated signaling suppresses the <italic>in vivo</italic> production of IL-10, which is a strong anti-inflammatory cytokine. The elevated IL-10 production in the peritoneal cells of Tyk2-deficient mice are alleviated by treatment with either diclofenac, a cyclooxygenase inhibitor, or H-89, a protein kinase A inhibitor. Notably, significantly higher basal prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) production is observed in peritoneal cavity of Tyk2-deficient mice than that of wild-type mice. Phosphorylation of cAMP response element-binding protein, induced by <italic>P. acnes</italic> and PGE<sub>2</sub> addition, is upregulated in Tyk2-deficient macrophages. This indicates that higher IL-10 production in Tyk2-deficient mice is likely a result of the enhanced PGE<sub>2</sub>-protein kinase A pathway. Thus, Tyk2-mediated signaling regulates multiple events during immune and/or inflammatory responses. </abstract>
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