Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation--a potential mechanism.
Macrophages accumulate in areas of inflammation and necrosis that are likely to be hypoxic. Chemotaxis of monocytes and macrophages towards chemokines is rapidly (within 60-90 min) inhibited by hypoxia. Exposure to the inflammatory cytokine TNF-alpha has a similar effect on monocyte migration. We report here that neither changes in mitochondrial respiration nor intracellular pH are involved in migration arrest. However, hypoxic inhibition of migration was mimicked using chemical activators of hypoxia-inducible factor-1 and reversed by transcriptional inhibition. We used RNA arbitrarily primed PCR, a differential display technique, to investigate which genes were up-regulated within 90-min exposure to hypoxia. Of several thousand mRNA screened, only one was consistently up-regulated by hypoxia and this was identified as MAPK phosphatase 1 (MKP-1), which modulates MAPK activity. Levels of MKP-1 mRNA and protein were rapidly elevated in monocytic cells and primary macrophages after hypoxia or TNF-alpha treatment. The functional significance of MKP-1 was illustrated by hypoxia-induced decreases in phosphorylated MAPK in these cells and arrest of chemotaxis by MAPK inhibitors. We suggest that one of the important events in an 'emergency stop' response in monocytic cells and macrophages may be inhibition of the chemoattractant signaling cascade.
Grimshaw
M J
MJ
Biological Therapies Laboratory, Imperial Cancer Research Fund, London, UK. grimshaw@icrf.icnet.uk
Balkwill
F R
FR
D002374:Catalase / Q000494:pharmacology; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia; D002633:Chemotaxis; D003609:Dactinomycin / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation / Q000276:immunology*; D008264:Macrophages / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000502:physiology*; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D002374:Catalase; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D003676:Deferoxamine