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 , , , .
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 , , , .
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
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
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) .
MIF up-regulates TLR4
expression and this way promotes the production of
iNOS, COX-2 and proinflammatory
cytokines , , , , , , .
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
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
, . c-Jun is involved in
iNOS expression, whereas
C/EBPbeta is a key factor involved in
COX-2 expression , , . Acetylation of C/EBPbeta by E1A binding protein
p300 (p300) is required for
COX-2 expression , .
Mitogen-activated protein kinase p38 (p38 MAPK)
phosphorylated by MEK4(MAP2K4) is also required for
C/EBPbeta activation leading to
COX-2 expression , .
p38 MAPK also regulates the stability of
COX-2 mRNA .
MIF also suppresses cell apoptosis by inactivating Tumor
protein p53 (p53) functional activity and decreasing
p53 expression level , .
Inhibition of p53 function via
MIF induction of COX-2 is
likely to be an important mechanism of MIF action . COX-2 physically interacts with
p53 followed by inhibition of cell apoptosis , .
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