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Immune response IL-12-induced IFN-gamma production

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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].