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

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...

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Bibliographic Details
Published in:	Journal of leukocyte biology Vol. 79; no. 1; pp. 147 - 154
Main Authors:	Han, Hyunsil, Roberts, Julia, Lou, Olivia, Muller, Willam A., Nathan, Noah, Nathan, Carl
Format:	Journal Article
Language:	English
Published:	United States Society for Leukocyte Biology 01-01-2006
Subjects:	Bacteria - growth & development Bacteria - immunology Cell Adhesion - drug effects Cell Adhesion - immunology Cell Degranulation - drug effects Cell Degranulation - immunology Cell Movement - drug effects Cell Movement - immunology Cells, Cultured Colony Count, Microbial Cytoskeleton - drug effects Cytoskeleton - immunology Endothelial Cells - cytology Endothelial Cells - immunology Heterocyclic Compounds - pharmacology Humans Neutrophils - cytology Neutrophils - immunology Peptides - pharmacology phox Protein-Tyrosine Kinases - immunology respiratory burst Respiratory Burst - drug effects Respiratory Burst - immunology Signal Transduction - drug effects Signal Transduction - immunology tumor necrosis factor Tumor Necrosis Factor-alpha - antagonists & inhibitors Tumor Necrosis Factor-alpha - immunology Tumor Necrosis Factor-alpha - pharmacology
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0741-5400 1938-3673
DOI:	10.1189/jlb.0605308