Pathway Map Details

Immune response_MIF in innate immunity response

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NF-kB p50/p65, COX-2, TAB2, I-kB, TNF-alpha, MIF, C/EBPbeta, p38 MAPK, IFN-gamma,, TAB1, IL-8, p53, Arachidonic acid,, CD14, MEK4(MAP2K4), iNOS, NO, IRAK4, JNK(MAPK8-10), (L)-Arginine, p300, LBP, MD-2, MEKK1(MAP3K1), c-Jun, MyD88, SITPEC (ECSIT), PU.1, IL-6, Prostaglandin G2, IRAK1/2, IKK-beta, TAK1(MAP3K7), LPS, IL-1 beta, TLR4, TRAF6, IKK (cat)


MIF in innate immunity response

The cytokine Macrophage migration inhibitory factor ( MIF ) is an integral mediator of the innate immune system. Monocytes, macrophages and lymphocytes constitutively express MIF, which is rapidly released after exposure to bacterial toxins and cytokines. MIF exerts potent proinflammatory activities and is an important cytokine of septic shock [1], [2], [3], [4].

MIF modulates innate immune responses to Lipopolysaccharide ( LPS ), endotoxin of gram-negative bacteria, by upregulating the expression of Toll-like receptor-4 ( TLR4 ) via activation of the transcription factor Spleen focus forming virus proviral integration oncogene spi1 ( PU.1 ) required for optimal expression of the TLR4 gene in myeloid cells [5], [3], [4], [6].

TLR4 is the signal-transducing receptor activated by the bacterial LPS. Firstly, LPS is delivered to CD14 receptor by Lipopolysaccharide binding protein ( LBP ), and CD14 then transfers it to TLR4. TLR4 homodimerizes and forms a complex with the Lymphocyte antigen 96 ( MD2 ) in order to recognize LPS.

Activated TLR4 binds to the adaptor protein Myeloid differentiation primary response gene 88 ( MyD88 ) that recruits Interleukin-1 receptor-associated kinase 4 ( IRAK4 ) and Interleukin-1 receptor-associated kinases 1 and 2 ( IRAK1/2 ). IRAK4 then phosphorylates IRAK1/2 kinases that associate with TNF receptor-associated factor 6 ( TRAF6 ), leading to the activation of two distinct signaling pathways, Nuclear factor kappa-B ( NF-kB p50/p65 ) and Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ).

TRAF6 forms a complex with Mitogen-activated protein kinase kinase kinase 7 interacting proteins 1 and 2 ( TAB1 and TAB2 ) and Mitogen-activated protein kinase kinase kinase 7 ( TAK1 ). TAK1 phosphorylates the Inhibitor of kappa light polypeptide gene enhancer in B-cells kinase beta ( IKK-beta ), a subunit of IKK complex catalytic core ( IKK (cat) ). The latter phosphorylates the Inhibitor of NF-kB ( I-kB ), leading to its ubiquitination and subsequent degradation. This allows NF-kB p50/p65 to translocate to the nucleus and induce the expression of Nitric oxide synthase 2A ( iNOS ), Prostaglandin-endoperoxide synthase 2 ( COX-2 ) and proinflammatory cytokines, such as Tumor necrosis factor ( TNF-alpha ), Interleukin 1 beta ( IL-1 beta ), Interleukin 6 ( IL-6 ), Interleukin 8 ( IL-8 ) and Interferon gamma ( IFN-gamma ) [7].

MIF up-regulates TLR4 expression and this way promotes the production of iNOS, COX-2 and proinflammatory cytokines [8], [9], [5], [3], [4], [6], [10].

Another signaling pathway, TRAF6/ SITPEC (ECSIT)/ Mitogen-activated protein kinase kinase kinase 1 ( MEKK1(MAP3K1) )/ IKK (cat)/ I-kB, also mediates the activation of NF-kB p50/p65 [7].

MEKK1(MAP3K1) also phosphorylates Mitogen-activated protein kinase kinase 4 ( MEK4(MAP2K4) ) which, in turn, phosphorylates JNK(MAPK8-10), leading to phosphorylation and activation of Jun oncogene ( c-Jun ) and CCAAT/enhancer binding protein beta ( C/EBPbeta ) transcription factors [7], [11]. c-Jun is involved in iNOS expression, whereas C/EBPbeta is a key factor involved in COX-2 expression [12], [13], [11]. Acetylation of C/EBPbeta by E1A binding protein p300 ( p300 ) is required for COX-2 expression [14], [15].

Mitogen-activated protein kinase p38 ( p38 MAPK ) phosphorylated by MEK4(MAP2K4) is also required for C/EBPbeta activation leading to COX-2 expression [16], [17]. p38 MAPK also regulates the stability of COX-2 mRNA [18].

MIF also suppresses cell apoptosis by inactivating Tumor protein p53 ( p53 ) functional activity and decreasing p53 expression level [19], [20]. Inhibition of p53 function via MIF induction of COX-2 is likely to be an important mechanism of MIF action [19]. COX-2 physically interacts with p53 followed by inhibition of cell apoptosis [21], [22].


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