title: Human neutrophil activation with interleukin-1. A role for intracellular calcium and arachidonic acid lipoxygenation.
abstract: Human monocyte-derived interleukin-1 (IL-1) stimulated the selective extracellular release of cytoplasmic granule-associated elastase from human neutrophils. Although extracellular calcium (Ca2+) enhances but is not required for the expression of granule exocytosis, IL-1 did induce the mobilization of previously sequestered intracellular Ca2+ as measured with the highly selective fluorescent Ca2+ indicator, Quin 2. Further, IL-1 stimulated the mobilization of cell membrane-associated Ca2+ as monitored by a decrease in fluorescence of chlorotetracycline (CTC)-loaded neutrophils. W-7, a calmodulin antagonist, and TMB-8[8(N,N-diethylamino)-octyl-(3,4,5-trimethoxy)benzoate hydrochloride], an intracellular Ca2+ antagonist, inhibited the Quin 2 fluorescent response by neutrophils to IL-1. TPCK (N-alpha-p-tosyl-L-lysine chloromethylketone), a serine protease inhibitor, suppressed IL-1-induced Quin 2 and CTC fluorescence. Exposure of neutrophils to IL-1 resulted in a concentration-dependent production of the 5-lipoxygenase product, LTB4 [5(S),12(R)-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid] which was enhanced in the presence of arachidonic acid (AA). LTB4 production by IL-1-activated neutrophils was suppressed by the lipoxygenase inhibitors nordihydroguaiaretic acid (NDGA) and piriprost potassium [6,9,deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin l1], and a cyclooxygenase/lipoxygenase inhibitor, 5,8,11,14-eicosatetraynoic acid (ETYA), whereas a cyclooxygenase inhibitor, flurbiprofen, was inactive. These data indicate that cytosolic free Ca2+ ([Ca2+]i) and a metabolite(s) of AA lipoxygenation mediate granule exocytosis elicited with IL-1.
authors.affiliation: Department of Hypersensitivity Diseases Research, Upjohn Co., Kalamazoo, MI 49001.
authors.forename: R J
authors.initials: RJ
authors.lastname: Smith
authors.forename: D E
authors.initials: DE
authors.lastname: Epps
authors.forename: J M
authors.initials: JM
authors.lastname: Justen
authors.forename: L M
authors.initials: LM
authors.lastname: Sam
authors.forename: M A
authors.initials: MA
authors.lastname: Wynalda
authors.forename: F A
authors.initials: FA
authors.lastname: Fitzpatrick
authors.forename: F S
authors.initials: FS
authors.lastname: Yein
mesh_terms: D015117:5,8,11,14-Eicosatetraynoic Acid / Q000378:metabolism; D000634:Aminoquinolines; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood*; D002118:Calcium / Q000097:blood*; D002751:Chlortetracycline / Q000378:metabolism; D003571:Cytochalasin B / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000096:biosynthesis; D008084:Lipoxygenase / Q000097:blood*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology
chemical_list: D000634:Aminoquinolines; D001095:Arachidonic Acids; D005456:Fluorescent Dyes; D007375:Interleukin-1; D013449:Sulfonamides; D015117:5,8,11,14-Eicosatetraynoic Acid; D007975:Leukotriene B4; D016718:Arachidonic Acid; D003571:Cytochalasin B; D014108:Tosylphenylalanyl Chloromethyl Ketone; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; C017967:W 7; D008084:Lipoxygenase; C035739:Quin2; D002118:Calcium; D002751:Chlortetracycline