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