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

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].

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References:

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