Involvement of leukotrienes, TNF-alpha, and the LFA-1/ICAM-1 interaction in substance P-induced granulocyte infiltration.
Substance P (SP) has been shown to mediate granulocyte infiltration into the mouse skin by inducing mast cell degranulation. In this study, using a variety of specific inhibitors, we investigated the cascade of events involved in the response of neutrophils and eosinophils to SP. The prostaglandin inhibitor, indomethacin, had little effect on SP-induced leukocyte migration. In contrast, pretreatment with the leukotriene (LT) synthesis inhibitor, A-64077, completely blocked neutrophil but not eosinophil migration in response to SP. Participation of tumor necrosis factor alpha (TNF-alpha) and LFA-1/ICAM-1 interaction was confirmed by inhibition of SP-induced leukocyte migration by pretreatment of mice with monoclonal antibodies to TNF-alpha, LFA-1, and ICAM-1. Moreover, alteration in leukocyte migration by indomethacin was found to depend on the concentration of TNF-alpha used. Indomethacin did not alter the number of leukocytes induced by low concentrations of TNF-alpha (0.1 ng), but reduced the number of cells stimulated with high TNF-alpha concentrations (1.0 ng). These results support the concept that SP modulates in vivo neuroinflammatory responses, as measured by granulocyte migration, initiating a cascade of events that includes LT production, TNF-alpha secretion, and engagement of LFA-1 and ICAM-1.
Saban
M R
MR
Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison 53706, USA.
Saban
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R
Bjorling
D
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Haak-Frendscho
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M
D000818:Animals; D000911:Antibodies, Monoclonal; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000502:physiology*; D015289:Leukotrienes / Q000502:physiology*; D016859:Lipoxygenase Inhibitors; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000166:cytology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D016861:Cyclooxygenase Inhibitors; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D016169:Lymphocyte Function-Associated Antigen-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D013373:Substance P; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases