Immune response - IL-23 signaling pathway

IL23 signaling pathway

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].

IL-23 receptor is composed of IL-12RB1 and IL23R. IL23R associates with JAK2 and in a ligand-dependent manner with STAT3 [2]. IL-12RB1 interacts directly with Tyk2 [3].

IL-23 binding to IL-23 receptor causes phosphorylation and activation of JAK-STAT signaling molecules: JAK2, Tyk2, and STAT1, STAT3, STAT4, STAT5. The most significant STAT induced by IL-23 is STAT3 [2].

IL-23 induced activation of STAT3 leads to direct binding of phosphorylated STAT3 to IL-17 and IL-17F promoters [4]. STAT3 also up-regulates the expression of ROR-gamma, a Th17 specific transcriptional regulator that is critical for the expression of two members of Interleukin-17 family, IL-17 and IL-17F [5], [6], [7].

IL-23 induced JAK2 activation triggers PI3K cat class IA/ AKT(PKB) and NF-kB p50/p65 pathways which are required for IL-17 production. AKT(PKB) can activate both NF-kB p50/p65 (IKK-alpha/ IKK (cat)/ I-kB pathway) and STAT3 (via an undetermined mechanism) [8], [9].

NF-kB p50/p65 binds IL17 promoter and up-regulates its expression [8].

SOCS3 may inhibit JAK2 activity, thereby decreasing IL-23 induced IL-17 and IL-17F expression [4].

Objects list:

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. Zou J, Presky DH, Wu CY, Gubler U
   Differential associations between the cytoplasmic regions of the interleukin-12 receptor subunits beta1 and beta2 and JAK kinases. The Journal of biological chemistry 1997 Feb 28;272(9):6073-7
4. 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
5. 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 Mar 30;282(13):9358-63
6. Laurence A, O'Shea JJ
   T(H)-17 differentiation: of mice and men. Nature immunology 2007 Sep;8(9):903-5
7. 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
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
9. 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