Immune response IL-12-induced IFN-gamma production

IL-12-induced IFN-gamma production

Interleukin 12 ( IL-12 ) is an important cytokine involved in production ofInterferon gamma ( IFN-gamma ) by T cells and NK cells, and plays an importantrole in differentiation of T helper 1 (Th1) cell population. IL-12 signaling workstogether with Interleukin 18 ( IL-18 ) and T-cell receptor ( TCR ) ininducing IFN- gamma production [1].

Upon binding to its receptor, IL-12 activates Janus family kinases Tyrosinekinase 2 ( Tyk2 ) and Janus kinase 2 ( Jak2 ). I nterleukin 12 receptorbeta 1 ( IL-12RBl ) binds Tyk2, whereas I nterleukin 12 receptor beta 2 (IL-12RB2 ) associates with Jak2, leading to phosphorylation of tyrosineresidues of Signal transducer and activator of transcription 3 and 4 ( STAT3 andSTAT4 ). These tyrosine phosphorylations are responsible for formation ofSTAT4/ STAT4 homodimer and STAT3/ STAT4 heterodimers. Thesedimers then translocate to the nucleus and bind to IFN-gamma promoter [2], [3], [4], [1].

Upon IL-12 action STAT4 induces transcription of Ets variant gene 5 (ERM ) and T-box 21 ( T-bet ), which also promote INF-gamma genetranscription [5], [6].

IL-12 in cooperation with IL-18 and TCR signaling inducesexpression and activation of Growth arrest and DNA-damage-inducible, beta and gamma (GADD45 beta, GADD45 gamma ).

IL-18 promotes expression of GADD45 beta in a Nuclear factor of kappalight polypeptide gene enhancer in B-cells ( NF-kB )-dependent manner. Interleukin18 receptor 1 ( IL-18R1 ), activated by IL-18, recruits Interleukin-1receptor-associated kinase 1 ( IRAK1 ) and TNF receptor-associated factor 6 (TRAF6 ). TRAF6 activates Mitogen-activated protein kinase kinase kinase 14( NIK(MAP3K14) ). This leads to subsequent activation of NF-kB, whichpromotes transcription of GADD45 beta [7], [8], [9].

GADD45 beta and GADD45 gamma activate Mitogen-activated protein kinasekinase kinase 4 ( MEKK4(MAP3K4) ). MEKK4(MAP3K4) phosphorylatesMitogen-activated protein kinase kinase 3 and 6 ( MEK3(MAP2K3) andMEK6(MAP2K6) ) and promotes Mitogen-activated protein kinase 14 ( p38alpha(MAPK14) ) activation. p38alpha (MAPK14) induces STAT4 Ser 721phosphorylation, which is important for IFN -gamma production. p38alpha(MAPK14) also phosphorylates Activating transcription factor 2 ( ATF-2 ) thatregulates IFN-gamma production independently of STAT4 [10],[11], [9], [12], [13].

IL-18 and TCR signaling, depending on co-stimulation of IL-12leads to activation of mitogen-activated protein kinase 8-10 ( JNK(MAPK8-10) ),also likely via GADD45 beta, gamma/ MEKK4(MAP3K4)/Mitogen-activated protein kinase kinase 4 ( MEK4(MAP2K4) ) pathway.JNK(MAPK8-10) phosphorylates Jun oncogene ( c-Jun ). Activated c-Juncooperates with STAT4 in IFN-gamma promoter activation [14],[15], [16], [17].

In addition, IL-12 action in NK cells promotes Nitric oxide synthase 2A (iNOS ) expression and Nitric oxide ( NO ) production, which is aprerequisite for activation of Tyk2, tyrosine phosphorylation of STAT4,and production of IFN-gamma [18], [19].

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 IFN{gamma}/Stat1 signals. Blood 2007 Jun 15;
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 1999 May 7;284(5416):951-5
19. Schindler H, Lutz MB, R?llinghoff 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