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

Authors


* John J. O'Shea
NIAMS, NIH, Bldg 10, Rm 9N256
10 Center Drive, MSC-1820
Bethesda, MD 20892-1820, USA
Tel.: +1 301 496 6026
Fax: +1 301 402 0012
E-mail: osheajo@mail.nih.gov

Abstract

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.

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