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Published online before print November 7, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0605308

Received for publication June 8, 2005.
Revised August 2, 2005.
Accepted for publication September 10, 2005.

Article

Chemical inhibitors of TNF signal transduction in human neutrophils point to distinct steps in cell activation

Hyunsil Han ^*, Julia Roberts ^*, Olivia Lou , Willam A. Muller , Noah Nathan , and Carl Nathan ^*@

Departments of *Microbiology and Immunology and Pathology and Laboratory Medicine, Weill Medical College of Cornell University, and Graduate Programs in Immunology and Microbial Pathogenesis and Molecular Biology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York

^@ To whom correspondence should be addressed. E-mail: cnathan{at}med.cornell.edu.

	Abstract

Chemical screening identified three small compounds that selectively inhibited activation of the respiratory burst (RB) of human neutrophils in response to tumor necrosis factor (TNF) and formylated peptide but not phorbol ester and spared the ability of neutrophils to kill bacteria. These compounds partially inhibited TNF-triggered cytoskeletal rearrangements without blocking adhesion or transmigation of polymorphonuclear neutrophils through TNF-activated monolayers of endothelial cells. The compounds were nontoxic to neutrophils and endothelial cells. They had no direct inhibitory effect on the tyrosine kinases Src, Syk, or Pyk2. However, their differential effects on cell spreading, bacteria-induced RB, TNF-induced degranulation, TNF-induced protein tyrosine phosphorylation, and TNF-induced Syk activation suggested that each may act on different elements of neutrophil signaling pathways.

Key Words: phox • respiratory burst • tumor necrosis factor

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