Diacylglycerols modulate human polymorphonuclear neutrophil responsiveness: effects on intracellular calcium mobilization, granule exocytosis, and superoxide anion production.
The synthetic diacylglycerols (DG), sn-1,2-dihexanoylglycerol (diC6), sn-1,2-dioctanoylglycerol (diC8), and 1-oleoyl-2-acetylglycerol (OAG) stimulated the release of granule constituents from and superoxide anion (O2-) generation by human polymorphonuclear neutrophils (PMN). The DGs did not induce a rise in the cytosolic-free calcium concentration ([Ca2+]i), as monitored by the fluorescence of PMNs loaded with the fluorescent CA2+ indicator, Fura-2. DiC6, diC8, and OAG inhibited PMN degranulation elicited with the receptor-specific ligands, N-formyl-methionyl-leucyl-phenylalanine (FMLP), acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC), and 5(S), 12(R)-dihydroxy-6,14-cis-8,10-trans eicosatetraenoic acid (LTB4) and the calcium ionophore, A23187. In contrast to their inhibitory effects on granule exocytosis, diC6, diC8 and OAG enhanced FMLP-, AGEPC-, LTB4 and A23187-stimulated O2- production. Activation of the respiratory burst with phorbol 12-myristate 13-acetate (PMA) was unaffected by the DGs. DiC8 inhibited the rise in [Ca2+]i elicited with FMLP, LTB4, and AGEPC; this effect, as well as the DG-mediated suppression of degranulation, could be reversed with the protein kinase C (PKC) inhibitor, 1-(-5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H-7). These data indicate that in addition to possessing the intrinsic capacity to activate PMNs, DG may function in a PKC-mediated autoregulatory mode to influence PMN activation in a response-specific manner by affecting certain components of receptor-coupled and receptor-independent signal transduction systems in a stimulus-specific manner.
Smith
R J
RJ
Department of Hypersensitivity Diseases Research, Upjohn Company, Kalamazoo, MI 49001.
Sam
L M
LM
Justen
J M
JM
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001572:Benzofurans; D002118:Calcium / Q000097:blood*; D003571:Cytochalasin B / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects; D004075:Diglycerides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis; D016257:Fura-2; D005989:Glycerides / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D013481:Superoxides / Q000097:blood*
D001572:Benzofurans; D004075:Diglycerides; D005989:Glycerides; D007546:Isoquinolines; D010879:Piperazines; D010972:Platelet Activating Factor; C044295:1,2-dioctanoylglycerol; D013481:Superoxides; D007975:Leukotriene B4; D003571:Cytochalasin B; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002118:Calcium; D016257:Fura-2