Regulation of IL-1 and TNF receptor expression and function by endogenous macrophage migration inhibitory factor.
Macrophage migration inhibitory factor (MIF) has a key role in regulation of innate and adaptive immunity and is implicated in sepsis, tumorigenesis, and autoimmune disease. MIF deficiency or immunoneutralization leads to protection against fatal endotoxic, exotoxic, and infective shock, and anti-inflammatory effects in other experimental models of inflammatory disease. We report a novel regulatory role of MIF in type 1 IL-1R and p55 TNFR expression and function. Compared with wild-type cells, MIF-deficient cells were hyporesponsive to IL-1- and TNF-induced MAPK activity, AP-1 activity, and cellular proliferation, while NF-kappaB function was preserved. Hyporesponsiveness of MIF-deficient cells was associated with down-regulation of cytokine receptor expression, which was restored by reconstitution of either an upstream kinase of MAPK, MAPK/ERK kinase, or MIF. These data suggest that endogenous MIF is required for cytokine activation of MAPK/AP-1 and cytokine receptor expression. This autocrine regulatory pathway defines an important amplifying role of endogenous MIF in cytokine-mediated immune and inflammatory diseases and provides further molecular evidence for the critical role of MIF in cellular activation.
Toh
Myew-Ling
ML
Centre for Inflammatory Diseases, Monash Institute of Medical Research, Monash Medical Center, Clayton, Melbourne 3168, Australia.
Aeberli
Daniel
D
Lacey
Derek
D
Yang
Yuan
Y
Santos
Leilani L
LL
Clarkson
Michael
M
Sharma
Laveena
L
Clyne
Colin
C
Morand
Eric F
EF
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D007375:Interleukin-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007375:Interleukin-1; D015850:Interleukin-6; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D018121:Receptors, Cytokine; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases