Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Immune response MIF in innate immunity response

Log In to Post A Comment

Immune response MIF in innate immunity response

MIF in innate immunity response

The cytokine Macrophage migration inhibitory factor ( MIF ) is an integralmediator of the innate immune system. Monocytes, macrophages and lymphocytesconstitutively express MIF, which is rapidly released after exposure to bacterialtoxins and cytokines. MIF exerts potent proinflammatory activities and is animportant 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-likereceptor-4 ( TLR4 ) via activation of the transcription factor Spleen focusforming virus proviral integration oncogene spi1 ( PU.1 ) required for optimalexpression 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 bindingprotein ( LBP ), and CD14 then transfers it to TLR4. TLR4homodimerizes and forms a complex with the Lymphocyte antigen 96 ( MD2 ) in orderto recognize LPS.

Activated TLR4 binds to the adaptor protein Myeloid differentiation primaryresponse gene 88 ( MyD88 ) that recruits Interleukin-1 receptor-associated kinase4 ( IRAK4 ) and Interleukin-1 receptor-associated kinases 1 and 2 ( IRAK1/2). IRAK4 then phosphorylates IRAK1/2 kinases that associate with TNFreceptor-associated factor 6 ( TRAF6 ), leading to the activation of two distinctsignaling pathways, Nuclear factor kappa-B ( NF-kB p50/p65 ) and Mitogen-activatedprotein kinases 8-10 ( JNK(MAPK8-10) ).

TRAF6 forms a complex with Mitogen-activated protein kinase kinase kinase 7interacting proteins 1 and 2 ( TAB1 and TAB2 ) and Mitogen-activatedprotein kinase kinase kinase 7 ( TAK1 ). TAK1 phosphorylates the Inhibitorof kappa light polypeptide gene enhancer in B-cells kinase beta ( IKK-beta ), asubunit of IKK complex catalytic core ( IKK (cat) ). The latter phosphorylates theInhibitor of NF-kB ( I-kB ), leading to its ubiquitination and subsequentdegradation. This allows NF-kB p50/p65 to translocate to the nucleus and inducethe expression of Nitric oxide synthase 2A ( iNOS ), Prostaglandin-endoperoxidesynthase 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 ofiNOS, COX-2 and proinflammatory cytokines [8], [9], [5], [3], [4], [6], [10].

Another signaling pathway, TRAF6/ SITPEC (ECSIT)/ Mitogen-activatedprotein 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 tophosphorylation and activation of Jun oncogene ( c-Jun ) and CCAAT/enhancerbinding protein beta ( C/EBPbeta ) transcription factors [7], [11]. c-Jun is involved in iNOS expression, whereas C/EBPbetais 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 byMEK4(MAP2K4) is also required for C/EBPbeta activation leading toCOX-2 expression [16], [17]. p38 MAPK alsoregulates 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 inductionof COX-2 is likely to be an important mechanism of MIF action [19]. COX-2 physically interacts with p53 followed by inhibition ofcell apoptosis [21], [22].