Human monocytes respond to leukotriene B4 with a transient increase in cytosolic calcium.
To define the intracellular activation events stimulated by leukotriene B4 (LTB4) in human monocytes, we investigated the transient increase in cytosolic free calcium levels ([Ca2+]i) elicited by this lipid mediator. Using elutriated human monocytes, LTB4 caused a dose-dependent increase in [Ca2+]i with an ED50 of 1.0 nM. The LTB4-induced [Ca2+]i response exhibited ligand selectivity, with both the diastereomer 5S-12S-diHETE and the 20-COOH LTB4 inactive at 500 nM, while 20-OH LTB4 was a partial agonist with an approximate ED50 of 10 nM. This response demonstrated stimulus-specific deactivation and was inhibited by the specific LTB4 receptor antagonist LY-223982. These results suggest that LTB4 stimulated an increase in [Ca2+]i via interaction with a defined LTB4 receptor. The inhibitory effects of pertussis toxin and PMA on the LTB4-induced [Ca2+]i suggest that a receptor-linked guanine nucleotide-binding protein and protein kinase C are involved in the regulation of the LTB4-elicited increase in [Ca2+]i. The LTB4-induced cell activation event may play a key role in the functional responses elicited by LTB4 in human monocytes.
Rediske
J
J
Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07901.
Morrissey
M M
MM
Jarvis
M
M
D001577:Benzophenones / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects*; D037342:Pertussis Toxin; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology; D018102:Receptors, Leukotriene B4; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D001577:Benzophenones; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; D010566:Virulence Factors, Bordetella; C065916:LY 223982; D007975:Leukotriene B4; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium