Immune response - IL-12-induced IFN-gamma production

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IL-12-induced IFN-gamma production

IL-12 is an important cytokine involved in production of IFN-gamma by T cells and NK cells, and plays an important role in T-helper cell differentiation. IL-12 signaling works together with IL-18 and TCR alpha/beta in inducing IFN-gamma production [1].

Upon binding to its receptor, IL-12 activates Janus family kinases Tyk2 and JAK2. IL-12RB1 binds Tyk2, whereas IL-12RB2 associates with JAK2, leading to phosphorylation of tyrosine residues of STAT3 and STAT4. These tyrosine phosphorylations are responsible for formation of STAT4/STAT4 homodimers and STAT3/STAT4 heterodimers. These dimers then translocate to the nucleus and bind to IFN-gamma promoter [1], [2], [3], [4].

Upon IL-12 action, STAT4 induces transcription of ERM and T-bet, which also promote IFN-gamma gene transcription [5], [6].

IL-12 in cooperation with IL-18 and TCR alpha/beta signaling induces expression and activation of GADD45 beta and GADD45 gamma.

IL-18 promotes expression of GADD45 beta in a NF-kB-dependent manner. IL-18R1, activated by IL-18, recruits IRAK1 and TRAF6. TRAF6 activates NIK(MAP3K14). This leads to subsequent activation of NF-kB, which promotes transcription of GADD45 beta [7], [8], [9].

GADD45 beta and GADD45 gamma activate MEKK4(MAP3K4). MEKK4(MAP3K4) phosphorylates MEK3(MAP2K3) and MEK6(MAP2K6) and promotes p38alpha (MAPK14) activation. p38alpha (MAPK14) induces STAT4 Ser 721 phosphorylation, which is important for IFN-gamma production. p38alpha (MAPK14) also phosphorylates ATF-2 that regulates IFN-gamma production independently of STAT4 [9], [10], [11], [12], [13].

IL-18 and TCR alpha/beta signaling, depending on co-stimulation of IL-12 leads to activation of JNK(MAPK8-10), also likely via GADD45 beta and/or GADD45 gamma/ MEKK4(MAP3K4)/ MEK4(MAP2K4) pathway. JNK(MAPK8-10) phosphorylates c-Jun. Activated c-Jun cooperates with STAT4 in IFN-gamma promoter activation [14], [15], [16], [17].

In addition, IL-12 action in NK cells promotes iNOS expression and iNOS production, which is a prerequisite for activation of Tyk2, tyrosine phosphorylation of STAT4, and production of IFN-gamma [18], [19].



Objects list:

ATF-2 Cyclic AMP-dependent transcription factor ATF-2
ERM ETS translocation variant 5
GADD45 beta Growth arrest and DNA damage-inducible protein GADD45 beta
GADD45 gamma Growth arrest and DNA damage-inducible protein GADD45 gamma
IFN-gamma Interferon gamma
IL-12 IL-12 Complex
IL-12RB1 Interleukin-12 receptor subunit beta-1
IL-12RB2 Interleukin-12 receptor subunit beta-2
IL-18 Interleukin-18
IL-18R1 Interleukin-18 receptor 1
IRAK1 Interleukin-1 receptor-associated kinase 1
JAK2 Tyrosine-protein kinase JAK2
JNK(MAPK8-10) c-Jun N-terminal kinases Protein group
MEK3(MAP2K3) Dual specificity mitogen-activated protein kinase kinase 3
MEK4(MAP2K4) Dual specificity mitogen-activated protein kinase kinase 4
MEK6(MAP2K6) Dual specificity mitogen-activated protein kinase kinase 6
MEKK4(MAP3K4) Mitogen-activated protein kinase kinase kinase 4
NF-kB NF-kB Group of complexes
NIK(MAP3K14) Mitogen-activated protein kinase kinase kinase 14
STAT3 Signal transducer and activator of transcription 3
STAT4 Signal transducer and activator of transcription 4
T-bet T-box transcription factor TBX21
TCR alpha/beta TCR alpha/beta Group of complexes
TRAF6 TNF receptor-associated factor 6
Tyk2 Non-receptor tyrosine-protein kinase TYK2
c-Jun Transcription factor AP-1
iNOS Nitric oxide synthase, inducible
p38alpha (MAPK14) Mitogen-activated protein kinase 14

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. Ouyang W, Jacobson NG, Bhattacharya D, Gorham JD, Fenoglio D, Sha WC, Murphy TL, Murphy KM
    The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. Proceedings of the National Academy of Sciences of the United States of America 1999 Mar 30;96(7):3888-93
  6. Yang Y, Ochando JC, Bromberg JS, Ding Y
    Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNgamma/Stat1 signals. Blood 2007 Oct 1;110(7):2494-500
  7. Kojima H, Takeuchi M, Ohta T, Nishida Y, Arai N, Ikeda M, Ikegami H, Kurimoto M
    Interleukin-18 activates the IRAK-TRAF6 pathway in mouse EL-4 cells. Biochemical and biophysical research communications 1998 Mar 6;244(1):183-6
  8. Dinarello CA
    Interleukin-18. Methods (San Diego, Calif.) 1999 Sep;19(1):121-32
  9. Yang J, Zhu H, Murphy TL, Ouyang W, Murphy KM
    IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN-gamma production. Nature immunology 2001 Feb;2(2):157-64
  10. Zhang S, Kaplan MH
    The p38 mitogen-activated protein kinase is required for IL-12-induced IFN-gamma expression. Journal of immunology (Baltimore, Md. : 1950) 2000 Aug 1;165(3):1374-80
  11. Visconti R, Gadina M, Chiariello M, Chen EH, Stancato LF, Gutkind JS, O'Shea JJ
    Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood 2000 Sep 1;96(5):1844-52
  12. Morinobu A, Gadina M, Strober W, Visconti R, Fornace A, Montagna C, Feldman GM, Nishikomori R, O'Shea JJ
    STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 2002 Sep 17;99(19):12281-6
  13. Chi H, Lu B, Takekawa M, Davis RJ, Flavell RA
    GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. The EMBO journal 2004 Apr 7;23(7):1576-86
  14. Barbulescu K, Becker C, Schlaak JF, Schmitt E, Meyer zum Buschenfelde KH, Neurath MF
    IL-12 and IL-18 differentially regulate the transcriptional activity of the human IFN-gamma promoter in primary CD4+ T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 1998 Apr 15;160(8):3642-7
  15. Zhang F, Nakamura T, Aune TM
    TCR and IL-12 receptor signals cooperate to activate an individual response element in the IFN-gamma promoter in effector Th cells. Journal of immunology (Baltimore, Md. : 1950) 1999 Jul 15;163(2):728-35
  16. Lu B, Yu H, Chow C, Li B, Zheng W, Davis RJ, Flavell RA
    GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. Immunity 2001 May;14(5):583-90
  17. Park WR, Nakahira M, Sugimoto N, Bian Y, Yashiro-Ohtani Y, Zhou XY, Yang YF, Hamaoka T, Fujiwara H
    A mechanism underlying STAT4-mediated up-regulation of IFN-gamma induction inTCR-triggered T cells. International immunology 2004 Feb;16(2):295-302
  18. Diefenbach A, Schindler H, Rollinghoff M, Yokoyama WM, Bogdan C
    Requirement for type 2 NO synthase for IL-12 signaling in innate immunity. Science (New York, N.Y.) 1999 May 7;284(5416):951-5
  19. Schindler H, Lutz MB, Rollinghoff M, Bogdan C
    The production of IFN-gamma by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4. Journal of immunology (Baltimore, Md. : 1950) 2001 Mar 1;166(5):3075-82

  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. Ouyang W, Jacobson NG, Bhattacharya D, Gorham JD, Fenoglio D, Sha WC, Murphy TL, Murphy KM
    The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. Proceedings of the National Academy of Sciences of the United States of America 1999 Mar 30;96(7):3888-93
  6. Yang Y, Ochando JC, Bromberg JS, Ding Y
    Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNgamma/Stat1 signals. Blood 2007 Oct 1;110(7):2494-500
  7. Kojima H, Takeuchi M, Ohta T, Nishida Y, Arai N, Ikeda M, Ikegami H, Kurimoto M
    Interleukin-18 activates the IRAK-TRAF6 pathway in mouse EL-4 cells. Biochemical and biophysical research communications 1998 Mar 6;244(1):183-6
  8. Dinarello CA
    Interleukin-18. Methods (San Diego, Calif.) 1999 Sep;19(1):121-32
  9. Yang J, Zhu H, Murphy TL, Ouyang W, Murphy KM
    IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN-gamma production. Nature immunology 2001 Feb;2(2):157-64
  10. Zhang S, Kaplan MH
    The p38 mitogen-activated protein kinase is required for IL-12-induced IFN-gamma expression. Journal of immunology (Baltimore, Md. : 1950) 2000 Aug 1;165(3):1374-80
  11. Visconti R, Gadina M, Chiariello M, Chen EH, Stancato LF, Gutkind JS, O'Shea JJ
    Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood 2000 Sep 1;96(5):1844-52
  12. Morinobu A, Gadina M, Strober W, Visconti R, Fornace A, Montagna C, Feldman GM, Nishikomori R, O'Shea JJ
    STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 2002 Sep 17;99(19):12281-6
  13. Chi H, Lu B, Takekawa M, Davis RJ, Flavell RA
    GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. The EMBO journal 2004 Apr 7;23(7):1576-86
  14. Barbulescu K, Becker C, Schlaak JF, Schmitt E, Meyer zum Buschenfelde KH, Neurath MF
    IL-12 and IL-18 differentially regulate the transcriptional activity of the human IFN-gamma promoter in primary CD4+ T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 1998 Apr 15;160(8):3642-7
  15. Zhang F, Nakamura T, Aune TM
    TCR and IL-12 receptor signals cooperate to activate an individual response element in the IFN-gamma promoter in effector Th cells. Journal of immunology (Baltimore, Md. : 1950) 1999 Jul 15;163(2):728-35
  16. Lu B, Yu H, Chow C, Li B, Zheng W, Davis RJ, Flavell RA
    GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. Immunity 2001 May;14(5):583-90
  17. Park WR, Nakahira M, Sugimoto N, Bian Y, Yashiro-Ohtani Y, Zhou XY, Yang YF, Hamaoka T, Fujiwara H
    A mechanism underlying STAT4-mediated up-regulation of IFN-gamma induction inTCR-triggered T cells. International immunology 2004 Feb;16(2):295-302
  18. Diefenbach A, Schindler H, Rollinghoff M, Yokoyama WM, Bogdan C
    Requirement for type 2 NO synthase for IL-12 signaling in innate immunity. Science (New York, N.Y.) 1999 May 7;284(5416):951-5
  19. Schindler H, Lutz MB, Rollinghoff M, Bogdan C
    The production of IFN-gamma by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4. Journal of immunology (Baltimore, Md. : 1950) 2001 Mar 1;166(5):3075-82

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