TNF-alpha promotes a stop signal that inhibits neutrophil polarization and migration via a p38 MAPK pathway.
Neutrophils are a major component of the inflammatory response in patients with asthma and other inflammatory conditions. Proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), are increased in the airway of patients with severe asthma and have been implicated in the recruitment of neutrophils into areas of inflammation. Here, we show that TNF-alpha induces a stop signal that promotes firm neutrophil adhesion and inhibits neutrophil polarization and chemotaxis to chemoattractants including interleukin-8 and C5a. TNF-alpha treatment of neutrophils plated on a fibrinogen-coated surface promotes firm neutrophil adhesion and the formation of vinculin-containing focal complexes. TNF-alpha induces a more than tenfold increase in p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase phosphorylation. Inhibition of p38 MAPK in neutrophils treated with TNF-alpha causes neutrophil polarization and motility. These findings suggest that TNF-alpha initiates a stop signal through a p38 MAPK pathway, which may promote the retention of neutrophils in inflammatory sites. Together, our data suggest that inhibition of p38 MAPK may be an attractive target to limit inflammatory responses that are mediated by TNF-alpha.
Lokuta
Mary A
MA
Department of Pediatrics, University of Wisconsin, Madison, 53706, USA. malokuta@facstaff.wisc.edu
Huttenlocher
Anna
A
D001249:Asthma / Q000276:immunology / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D016764:Cell Polarity / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D015936:Complement C5a / Q000276:immunology / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D016209:Interleukin-8 / Q000276:immunology / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*
D004791:Enzyme Inhibitors; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D015936:Complement C5a; D048051:p38 Mitogen-Activated Protein Kinases