Pathway maps

Immune response_MIF in innate immunity response
Immune response_MIF in innate immunity response

Object List (links open in MetaCore):

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].


  1. Das UN
    Critical advances in septicemia and septic shock. Critical care (London, England) 2000;4(5):290-6
  2. Calandra T, Froidevaux C, Martin C, Roger T
    Macrophage migration inhibitory factor and host innate immune defenses against bacterial sepsis. The Journal of infectious diseases 2003 Jun 15;187 Suppl 2:S385-90
  3. Roger T, Froidevaux C, Martin C, Calandra T
    Macrophage migration inhibitory factor (MIF) regulates host responses to endotoxin through modulation of Toll-like receptor 4 (TLR4). Journal of endotoxin research 2003;9(2):119-23
  4. Calandra T
    Macrophage migration inhibitory factor and host innate immune responses to microbes. Scandinavian journal of infectious diseases 2003;35(9):573-6
  5. Roger T, David J, Glauser MP, Calandra T
    MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 2001 Dec 20-27;414(6866):920-4
  6. Ohkawara T, Takeda H, Miyashita K, Nishiwaki M, Nakayama T, Taniguchi M, Yoshiki T, Tanaka J, Imamura M, Sugiyama T, Asaka M, Nishihira J
    Regulation of Toll-like receptor 4 expression in mouse colon by macrophage migration inhibitory factor. Histochemistry and cell biology 2006 May;125(5):575-82
  7. Takeda K, Kaisho T, Akira S
    Toll-like receptors. Annual review of immunology 2003;21:335-76
  8. Froidevaux C, Roger T, Martin C, Glauser MP, Calandra T
    Macrophage migration inhibitory factor and innate immune responses to bacterial infections. Critical care medicine 2001 Jul;29(7 Suppl):S13-5
  9. Roger T, Glauser MP, Calandra T
    Macrophage migration inhibitory factor (MIF) modulates innate immune responses induced by endotoxin and Gram-negative bacteria. Journal of endotoxin research 2001;7(6):456-60
  10. Javeed A, Zhao Y, Zhao Y
    Macrophage-migration inhibitory factor: role in inflammatory diseases and graft rejection. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2008 Feb;57(2):45-50
  11. Lin MW, Tsao LT, Chang LC, Chen YL, Huang LJ, Kuo SC, Tzeng CC, Lee MR, Wang JP
    Inhibition of lipopolysaccharide-stimulated NO production by a novel synthetic compound CYL-4d in RAW 264.7 macrophages involving the blockade of MEK4/JNK/AP-1 pathway. Biochemical pharmacology 2007 Jun 1;73(11):1796-806
  12. Cho YH, Lee CH, Kim SG
    Potentiation of lipopolysaccharide-inducible cyclooxygenase 2 expression by C2-ceramide via c-Jun N-terminal kinase-mediated activation of CCAAT/enhancer binding protein beta in macrophages. Molecular pharmacology 2003 Mar;63(3):512-23
  13. Wu KK, Liou JY, Cieslik K
    Transcriptional Control of COX-2 via C/EBPbeta. Arteriosclerosis, thrombosis, and vascular biology 2005 Apr;25(4):679-85
  14. Deng WG, Zhu Y, Wu KK
    Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators. Blood 2004 Mar 15;103(6):2135-42
  15. Joo M, Park GY, Wright JG, Blackwell TS, Atchison ML, Christman JW
    Transcriptional regulation of the cyclooxygenase-2 gene in macrophages by PU.1. The Journal of biological chemistry 2004 Feb 20;279(8):6658-65
  16. Caivano M, Gorgoni B, Cohen P, Poli V
    The induction of cyclooxygenase-2 mRNA in macrophages is biphasic and requires both CCAAT enhancer-binding protein beta (C/EBP beta ) and C/EBP delta transcription factors. The Journal of biological chemistry 2001 Dec 28;276(52):48693-701
  17. Santos LL, Lacey D, Yang Y, Leech M, Morand EF
    Activation of synovial cell p38 MAP kinase by macrophage migration inhibitory factor. The Journal of rheumatology 2004 Jun;31(6):1038-43
  18. Gipstein RM, Coburn JW, Adams DA, Lee DB, Parsa KP, Sellers A, Suki WN, Massry SG
    Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure. Archives of internal medicine 1976 Nov;136(11):1273-80
  19. Mitchell RA, Liao H, Chesney J, Fingerle-Rowson G, Baugh J, David J, Bucala R
    Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proceedings of the National Academy of Sciences of the United States of America 2002 Jan 8;99(1):345-50
  20. Leech M, Lacey D, Xue JR, Santos L, Hutchinson P, Wolvetang E, David JR, Bucala R, Morand EF
    Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis. Arthritis and rheumatism 2003 Jul;48(7):1881-9
  21. Corcoran CA, He Q, Huang Y, Sheikh MS
    Cyclooxygenase-2 interacts with p53 and interferes with p53-dependent transcription and apoptosis. Oncogene 2005 Feb 24;24(9):1634-40
  22. Choi EM, Heo JI, Oh JY, Kim YM, Ha KS, Kim JI, Han JA
    COX-2 regulates p53 activity and inhibits DNA damage-induced apoptosis. Biochemical and biophysical research communications 2005 Mar 25;328(4):1107-12