title: Chemical inhibitors of TNF signal transduction in human neutrophils point to distinct steps in cell activation.
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.
authors.affiliation: Department of Microbiology and Immunobiology, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Hyunsil
authors.initials: H
authors.lastname: Han
authors.forename: Julia
authors.initials: J
authors.lastname: Roberts
authors.forename: Olivia
authors.initials: O
authors.lastname: Lou
authors.forename: Willam A
authors.initials: WA
authors.lastname: Muller
authors.forename: Noah
authors.initials: N
authors.lastname: Nathan
authors.forename: Carl
authors.initials: C
authors.lastname: Nathan
mesh_terms: D001419:Bacteria / Q000254:growth & development / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D003599:Cytoskeleton / Q000187:drug effects / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D010455:Peptides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D016897:Respiratory Burst / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology
chemical_list: D006571:Heterocyclic Compounds; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases