Published online before print April 21, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0205067

Received for publication February 2, 2005.
Revised March 18, 2005.
Accepted for publication March 25, 2005.

Article

TNF- promotes a stop signal that inhibits neutrophil polarization and migration via a p38 MAPK pathway

Mary A. Lokuta ^*@ and Anna Huttenlocher ^*

Departments of *Pediatrics and Pharmacology, University of Wisconsin, Madison

^@ To whom correspondence should be addressed. E-mail: malokuta{at}facstaff.wisc.edu.

Abstract

Neutrophils are a major component of the inflammatory response in patients with asthma and other inflammatory conditions. Proinflammatory cytokines, such as tumor necrosis factor (TNF-), 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- induces a stop signal that promotes firm neutrophil adhesion and inhibits neutrophil polarization and chemotaxis to chemoattractants including interleukin-8 and C5a. TNF- treatment of neutrophils plated on a fibrinogen-coated surface promotes firm neutrophil adhesion and the formation of vinculin-containing focal complexes. TNF- 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- causes neutrophil polarization and motility. These findings suggest that TNF- 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-.

Key Words: chemotaxis • inflammation • asthma

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