Signaling by IL‐12 and IL‐23 and the immunoregulatory roles of STAT4

Summary: Produced in response to a variety of pathogenic organisms, interleukin (IL)‐12 and IL‐23 are key immunoregulatory cytokines that coordinate innate and adaptive immune responses. These dimeric cytokines share a subunit, designated p40, and bind to a common receptor chain, IL‐12Rβ1. The receptor for IL‐12 is composed of IL‐12Rβ1 and IL‐12Rβ2, whereas IL‐23 binds to a receptor composed of IL‐12Rβ1 and IL‐23R. Both cytokines activate the Janus kinases Tyk2 and Jak2, the transcription factor signal transducer and activator of transcription 4 (STAT4), as well as other STATs. A major action of IL‐12 is to promote the differentiation of naïve CD4 + T cells into T‐helper (Th) 1 cells, which produce interferon (IFN)‐γ, and deficiency of IL‐12, IL‐12R subunits or STAT4 is similar in many respects. In contrast, IL‐23 promotes end‐stage inflammation. Targeting IL‐12, IL‐23, and their downstream signaling elements would therefore be logical strategies for the treatment of immune‐mediated diseases.