Pathway Map Details

Immune response_IL-12-induced IFN-gamma production

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Object list (links open in MetaCore):

NO, IL-18R1, NF-kB, ATF-2, IL-18,, STAT3, GADD45 gamma, GADD45 beta, IL-12, TRAF6, Tyk2, T-bet, IL-12 receptor, MEK3 (MAP2K3), CD3, IFN-gamma, (L)-Arginine, p38alpha (MAPK14), IL-12RB1, IL-12RB2, MEK4 (MAP2K4), iNOS, NIK(MAP3K14), MEK6 (MAP2K6), TCR alpha/beta, IKK (cat), (L)-Citrulline cytosol, IRAK1, I-kB, MEKK4 (MAP3K4), c-Jun, JAK2, STAT4, ERM, JNK(MAPK8-10)


IL-12-induced IFN-gamma production

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

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 Tyk2, whereas I nterleukin 12 receptor beta 2 ( IL-12RB2 ) associates with Jak2, leading to phosphorylation of tyrosine residues of Signal transducer and activator of transcription 3 and 4 ( STAT3 and STAT4 ). These tyrosine phosphorylations are responsible for formation of STAT4/ STAT4 homodimer and STAT3/ STAT4 heterodimers. These dimers 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 gene transcription [5], [6].

IL-12 in cooperation with IL-18 and TCR signaling induces expression 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 kappa light polypeptide gene enhancer in B-cells ( NF-kB )-dependent manner. Interleukin 18 receptor 1 ( IL-18R1 ), activated by IL-18, recruits Interleukin-1 receptor-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, which promotes transcription of GADD45 beta [7], [8], [9].

GADD45 beta and GADD45 gamma activate Mitogen-activated protein kinase kinase kinase 4 ( MEKK4(MAP3K4) ). MEKK4(MAP3K4) phosphorylates Mitogen-activated protein kinase kinase 3 and 6 ( MEK3(MAP2K3) and MEK6(MAP2K6) ) and promotes Mitogen-activated protein kinase 14 ( p38alpha (MAPK14) ) activation. p38alpha (MAPK14) induces STAT4 Ser 721 phosphorylation, which is important for IFN -gamma production. p38alpha (MAPK14) also phosphorylates Activating transcription factor 2 ( ATF-2 ) that regulates IFN-gamma production independently of STAT4 [10], [11], [9], [12], [13].

IL-18 and TCR signaling, depending on co-stimulation of IL-12 leads 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-Jun cooperates 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 a prerequisite for activation of Tyk2, tyrosine phosphorylation of STAT4, and production of IFN-gamma [18], [19].


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