Pathway maps

Immune response_IL-23 signaling pathway
Immune response_IL-23 signaling pathway

Object List (links open in MetaCore):

STAT1, JAK2, STAT4, IL-23, PDK (PDPK1), PI3K cat class IA, STAT5, SOCS3, IL-17F, AKT(PKB), RelA (p65 NF-kB subunit), IL23R, PtdIns(3,4,5)P3, IL-23 receptor, STAT3, I-kB, PtdIns(4,5)P2, 2.7.1.153, PI3K reg class IA, NF-kB1 (p50), IL-12RB1, Tyk2, IL-17, ROR-gamma

Description

IL23 signaling pathway

Interleukin-23 ( IL-23 ) plays important role in expanding and maintaining the Th17 cell population, a novel T-cell subset involved in antimicrobial immune response and establishment of many autoimmune diseases [1].

Interleukin-23 receptor ( IL-23 receptor ) is composed of Interleukin-12 receptor beta-1 ( IL-12RB1 ) chain and Interleukin 23 alpha subunit p19 ( IL23A ). IL23A associates with Janus kinase 2 ( Jak2 ) and in a ligand-dependent manner with Signal transducer and activator of transcription STAT3 [2]. IL-12RB1 interacts directly with Tyrosine kinase 2 ( Tyk2 ) [2].

IL-23 induced activation of STAT3 leads to direct binding of phosphorylated STAT3 to Interleukin-17 ( IL-17 ) and Interleukin 17F ( IL-17F ) promoters [3]. STAT3 up-regulates the expression of Retinoic Acid Receptor-Related Orphan Receptor Gamma-T ( ROR-gamma ), a Th17 specific transcriptional regulator that is critical for the expression of two members of Interleukin-17 family, IL-17A ( IL-17 ) and IL-17F [4], [5], [6].

IL-23 induced JAK2 activation triggers Phosphoinositide-3-kinase ( PI3K )/ RAC-alpha serine/threonine kinase ( AKT ) and Nuclear factor kappaB ( NF-kB ) pathways which are required for IL-17 production. PI3K/ AKT pathway is involved in STAT3 phosphorylation through an undetermined mechanism [7].

V-rel reticuloendotheliosis viral oncogene homolog A, nuclear factor of kappa light polypeptide gene enhancer in B-cells 3, p65 (avian) ( RelA (p65 NF-kB subunit) ) and Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105) ( NF-kB1 (p50) ) bind IL17 promoter and up-regulate its expression [8].

Suppressor of cytokine signaling 3 ( SOCS3 ) may inhibit JAK2 activity, thereby decreasing IL-23 induced IL-17 and IL-17F expression [3].

References:

  1. McGeachy MJ, Cua DJ
    Th17 cell differentiation: the long and winding road. Immunity 2008 Apr;28(4):445-53
  2. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW
    A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 1;168(11):5699-708
  3. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O'Shea JJ
    Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proceedings of the National Academy of Sciences of the United States of America 2006 May 23;103(21):8137-42
  4. Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C
    STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. The Journal of biological chemistry 2007 Feb 3;
  5. Laurence A, O'Shea JJ
    T(H)-17 differentiation: of mice and men. Nature immunology 2007 Sep;8(9):903-5
  6. Chen Z, Laurence A, O'Shea JJ
    Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Seminars in immunology 2007 Dec;19(6):400-8
  7. Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, Jin HT, Min SY, Ju JH, Park KS, Cho YG, Yoon CH, Park SH, Sung YC, Kim HY
    STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 2006 May 1;176(9):5652-61
  8. Kim KW, Cho ML, Park MK, Yoon CH, Park SH, Lee SH, Kim HY
    Increased interleukin-17 production via a phosphoinositide 3-kinase/Akt and nuclear factor kappaB-dependent pathway in patients with rheumatoid arthritis. Arthritis research & therapy 2005;7(1):R139-48