Pathway maps

Immune response_IL-12 signaling pathway
Immune response_IL-12 signaling pathway

Object List (links open in MetaCore):

PIAS2, IL-2R alpha chain, Perforin, IFN-gamma, c-Jun, JAK2, STAT3, IL-12RB1, SOCS3, IRF1, Tyk2, IL-12RB2, IRF4, P-selectin, IL-18R1, IL-12 receptor, STAT4, PDLIM2, G6NT, STAT5, Ubiquitin, STAT5A, IL-12

Description

IL-12 signaling pathway

Interleukin-12 ( IL-12 ) is a key immunoregulatory cytokine that coordinates innate and adaptive immune responses. Major event of IL-12 signaling is activation of Signal transducers and activators of transcription ( STAT s), mainly STAT4, to promote differentiation of native CD4+T cells into T-helper (Th) 1 cells, NK cellular cytotoxicity and proliferation of T cells [1].

The main role of IL-12 is activation of Interferon gamma ( IFN-gamma ) production. Upon binding to its receptor, IL-12 activates Janus family kinases Tyrosine kinase 2 ( Tyk2 ) and Janus kinase 2 ( Jak2 ). I nterleukin 12 receptor, beta 1 ( IL-12RBl ) binds the Tyk2, whereas I nterleukin 12 receptor, beta 2 ( IL-12RB2 ) associates with Jak2. Jak2 phosphorylates the tyrosine residues of STAT3 and STAT4. They translocate to the nucleus and bind to the promoter site of IFN-gamma. STAT4 also recruits Jun oncogene ( c-Jun ) to IFN-gamma promoter [2], [3], [4].

Upon IL-12 action, STAT4 also induces transcription of IL-12RB2 and Interleukin 18 receptor 1 ( IL-18RB1 ), that leads to amplification of IL-12 signaling and Th1 cells differentiation [5], [6], [7], [8], [9]. Also, IL-12 promotes expression of Interferon regulatory factor 1 ( IRF1 ) and 4 ( IRF4 ) in a STAT4 -dependent manner [10], [11].

In addition, IL-12 promotes expression of Interleukin 2 receptor, alpha ( IL-2R ) by recruiting STAT4 and c-Jun to the promoter of IL-2R and thereby enhancing T cell proliferation [12], [13].

In NK cells, IL-12 induce d cytotoxic events by STAT4 activation of Perforin 1 ( perforin ) gene at its promoter [14].

And lastly, IL-12 -induce d STAT4 activation leading to expression of GCNT1 glucosaminyl (N-acetyl) transferase 1 core 2 ( G6NT ), enzyme responsible for SELP selectin P (P-selectin ) ligand formation. This augments cell adhesion during T-cell differentiation [15], [16], [17], [18].

IL-12 has the capacity to induce STAT5 protein. JAK2 activation by IL-12R induces STAT5 phosphorylation thus promoting cellular proliferation [19]. However, there is evidence that STAT5A can suppress IL-12 -induced Th1 cell differentiation through the induction of Suppressor of cytokine signaling 3 ( SOCS3 ) expression. SOCS3 inhibits IL-12 signaling by binding to the STAT4 docking site of the IL-12RB2 subunit [20], [21].

Another negative regulator of IL-12 signaling is Protein inhibitor of activated STAT 2 ( PIAS2 ). It binds to STAT4 and represses its transcriptional activity [22].

It was shown that STAT4 undergoes proteosomal degradation during IL-12 signaling. PDZ and LIM domain 2 ( PDLIM2 ) was identified as an ubiquitin E3 ligase that acts on STAT4 protein to cause its proteosome-mediated degradation [23], [24].

References:

  1. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ
    Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunological reviews 2004 Dec;202:139-56
  2. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE Jr, Murphy KM
    Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. The Journal of experimental medicine 1995 May 1;181(5):1755-62
  3. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC, Ihle JN
    Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 1996 Jul 11;382(6587):171-4
  4. Kusaba H, Ghosh P, Derin R, Buchholz M, Sasaki C, Madara K, Longo DL
    Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR). The Journal of biological chemistry 2005 Jan 14;280(2):1037-43
  5. Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K
    IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. Journal of immunology (Baltimore, Md. : 1950) 1998 Oct 1;161(7):3400-7
  6. Nakahira M, Tomura M, Iwasaki M, Ahn HJ, Bian Y, Hamaoka T, Ohta T, Kurimoto M, Fujiwara H
    An absolute requirement for STAT4 and a role for IFN-gamma as an amplifying factor in IL-12 induction of the functional IL-18 receptor complex. Journal of immunology (Baltimore, Md. : 1950) 2001 Aug 1;167(3):1306-12
  7. Letimier FA, Passini N, Gasparian S, Bianchi E, Rogge L
    Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation. The EMBO journal 2007 Mar 7;26(5):1292-302
  8. Yu Q, Thieu VT, Kaplan MH
    Stat4 limits DNA methyltransferase recruitment and DNA methylation of the IL-18Ralpha gene during Th1 differentiation. The EMBO journal 2007 Apr 18;26(8):2052-60
  9. Becskei A, Grusby MJ
    Contribution of IL-12R mediated feedback loop to Th1 cell differentiation. FEBS letters 2007 Nov 13;581(27):5199-206
  10. Galon J, Sudarshan C, Ito S, Finbloom D, O'Shea JJ
    IL-12 induces IFN regulating factor-1 (IRF-1) gene expression in human NK and T cells. Journal of immunology (Baltimore, Md. : 1950) 1999 Jun 15;162(12):7256-62
  11. Lehtonen A, Lund R, Lahesmaa R, Julkunen I, Sareneva T, Matikainen S
    IFN-alpha and IL-12 activate IFN regulatory factor 1 (IRF-1), IRF-4, and IRF-8 gene expression in human NK and T cells. Cytokine 2003 Nov 7;24(3):81-90
  12. Yanagida T, Kato T, Igarashi O, Inoue T, Nariuchi H
    Second signal activity of IL-12 on the proliferation and IL-2R expression of T helper cell-1 clone. Journal of immunology (Baltimore, Md. : 1950) 1994 May 15;152(10):4919-28
  13. Foukas LC, Panayotou G, Shepherd PR
    Direct interaction of major histocompatibility complex class II-derived peptides with class Ia phosphoinositide 3-kinase results in dose-dependent stimulatory effects. The Journal of biological chemistry 2004 Feb 27;279(9):7505-11
  14. Yamamoto K, Shibata F, Miyasaka N, Miura O
    The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells. Biochemical and biophysical research communications 2002 Oct 11;297(5):1245-52
  15. Lim YC, Henault L, Wagers AJ, Kansas GS, Luscinskas FW, Lichtman AH
    Expression of functional selectin ligands on Th cells is differentially regulated by IL-12 and IL-4. Journal of immunology (Baltimore, Md. : 1950) 1999 Mar 15;162(6):3193-201
  16. White SJ, Underhill GH, Kaplan MH, Kansas GS
    Cutting edge: differential requirements for Stat4 in expression of glycosyltransferases responsible for selectin ligand formation in Th1 cells. Journal of immunology (Baltimore, Md. : 1950) 2001 Jul 15;167(2):628-31
  17. Lim YC, Xie H, Come CE, Alexander SI, Grusby MJ, Lichtman AH, Luscinskas FW
    IL-12, STAT4-dependent up-regulation of CD4(+) T cell core 2 beta-1,6-n-acetylglucosaminyltransferase, an enzyme essential for biosynthesis of P-selectin ligands. Journal of immunology (Baltimore, Md. : 1950) 2001 Oct 15;167(8):4476-84
  18. Underhill GH, Zisoulis DG, Kolli KP, Ellies LG, Marth JD, Kansas GS
    A crucial role for T-bet in selectin ligand expression in T helper 1 (Th1) cells. Blood 2005 Dec 1;106(12):3867-73
  19. Ahn HJ, Tomura M, Yu WG, Iwasaki M, Park WR, Hamaoka T, Fujiwara H
    Requirement for distinct Janus kinases and STAT proteins in T cell proliferation versus IFN-gamma production following IL-12 stimulation. Journal of immunology (Baltimore, Md. : 1950) 1998 Dec 1;161(11):5893-900
  20. Yamamoto K, Yamaguchi M, Miyasaka N, Miura O
    SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 domain to the STAT4 docking site in the IL-12 receptor beta2 subunit. Biochemical and biophysical research communications 2003 Oct 31;310(4):1188-93
  21. Takatori H, Nakajima H, Kagami S, Hirose K, Suto A, Suzuki K, Kubo M, Yoshimura A, Saito Y, Iwamoto I
    Stat5a inhibits IL-12-induced Th1 cell differentiation through the induction of suppressor of cytokine signaling 3 expression. Journal of immunology (Baltimore, Md. : 1950) 2005 Apr 1;174(7):4105-12
  22. Arora T, Liu B, He H, Kim J, Murphy TL, Murphy KM, Modlin RL, Shuai K
    PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4. The Journal of biological chemistry 2003 Jun 13;278(24):21327-30
  23. Wang KS, Zorn E, Ritz J
    Specific down-regulation of interleukin-12 signaling through induction of phospho-STAT4 protein degradation. Blood 2001 Jun 15;97(12):3860-6
  24. Tanaka T, Soriano MA, Grusby MJ
    SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling. Immunity 2005 Jun;22(6):729-36