title: U-73122: a potent inhibitor of human polymorphonuclear neutrophil adhesion on biological surfaces and adhesion-related effector functions.
abstract: We have reported that U-73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole- 2,5-dione) an inhibitor of phospholipase C-dependent processes in human polymorphonuclear neutrophils (PMN) and platelets, potently suppresses the responsiveness of suspended PMN and platelets to receptor agonists. We demonstrate here that U-73122 caused a concentration-dependent (10-800 nM) inhibition of N-formyl-methionyl-leucyl-phenylalanine, tumor necrosis factor-alpha (TNF alpha), interleukin-8 and phorbol myristate acetate (PMA)-triggered PMN adhesion on fibronectin, fetal bovine serum or keyhole limpet hemocyanincoated microtiter plates. U-73122 also inhibited PMN adherence to and transmigration through TNF-alpha-activated endothelium (IC50 < 50 nM). Further, U-73122 suppressed interleukin-8, N-formylmethionyl-leucyl-phenylalanine and PMA-stimulated up-regulation of the beta 2-integrin, Mac-1 (CD11b/CD18), on the PMN surface (IC50 < 1.3 microM). U-73122 also caused a time-(15-120 min) and concentration-dependent inhibition (IC50 = 25-100 nM) of the N-formyl-methionyl-leucyl-phenylalanine-, TNF alpha- and PMA-elicited adhesion-dependent, oxidative burst, measured as hydrogen peroxide (H2O2) production, in PMN. The CD18-dependent extracellular release of lactoferrin from PMN activated with these stimuli was also suppressed by U-73122. U-73343 (1-[6-[[17 beta-3- methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-2,5-pyrrolidine dione), a close analog of U-73122, did not affect PMN responsiveness.
authors.affiliation: Cell Biology and Inflammation Research, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Smith
authors.forename: J M
authors.initials: JM
authors.lastname: Justen
authors.forename: A R
authors.initials: AR
authors.lastname: McNab
authors.forename: C L
authors.initials: CL
authors.lastname: Rosenbloom
authors.forename: A N
authors.initials: AN
authors.lastname: Steele
authors.forename: P A
authors.initials: PA
authors.lastname: Detmers
authors.forename: D C
authors.initials: DC
authors.lastname: Anderson
authors.forename: A M
authors.initials: AM
authors.lastname: Manning
mesh_terms: D000818:Animals; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000494:pharmacology*; D006801:Humans; D009504:Neutrophils / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*
chemical_list: D004963:Estrenes; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione