Endogenous macrophage migration inhibitory factor modulates glucocorticoid sensitivity in macrophages via effects on MAP kinase phosphatase-1 and p38 MAP kinase.
The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) is induced by glucocorticoids (GCs), but it was not previously known if MIF regulates cellular sensitivity to GC. Here we show in GC and LPS-treated peritoneal macrophages derived from MIF-/- and wt mice that the absence of endogenous MIF is associated with increased sensitivity to GC of TNF release. This is associated with increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), concomitant decreased phosphorylation of p38 MAPK, but no effect of MIF on nuclear factor kappaB (NF-kappaB). These results demonstrate that MIF regulates GC sensitivity by phosphorylation of p38, and provides a cellular mechanism for this observation, indicating that MKP-1 is a central target of this regulation.
Aeberli
Daniel
D
Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, Clayton, Melbourne, Australia.
Yang
Yuan
Y
Mansell
Ashley
A
Santos
Lanie
L
Leech
Michelle
M
Morand
Eric F
EF
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1; D017874:Immediate-Early Proteins / Q000378:metabolism; D019746:Intramolecular Oxidoreductases; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse