Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4.
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-12R beta 1. The receptor for IL-12 is composed of IL-12R beta 1 and IL-12R beta 2, whereas IL-23 binds to a receptor composed of IL-12R beta 1 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 naive CD4+ T cells into T-helper (Th) 1 cells, which produce interferon (IFN)-gamma, 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.
Watford
Wendy T
WT
Molecular Immunology & Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892-1820, USA.
Hissong
Bruce D
BD
Bream
Jay H
JH
Kanno
Yuka
Y
Muul
Linda
L
O'Shea
John J
JJ
D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000172:deficiency / Q000502:physiology*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000172:deficiency / Q000502:physiology*; D018123:Receptors, Interleukin / Q000502:physiology; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology*; D015534:Trans-Activators / Q000737:chemistry / Q000172:deficiency / Q000276:immunology / Q000502:physiology*
D004268:DNA-Binding Proteins; C508840:IL23A protein, human; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12