Modulation of human basophil histamine release by protein kinase C inhibitors differs with secretagogue and with inhibitor.
To assess possible involvement of protein kinase C (PKC) in human basophil degranulation, the present work compared effects of various purported PKC inhibitors on leukocyte histamine release triggered by different stimuli. The effects recorded varied with the inhibitor and the secretagogue used; moreover, with a given secretagogue, different inhibitors often displayed different activities. Thus, histamine release triggered by the PKC activator 4 beta-phorbol 12-myristate 13-acetate was blocked by K252a, staurosporine and the purported specific PKC inhibitor Ro 31-7549, and reduced by calphostin C, H-7, TMB-8 and W-7 but not affected by polymyxin B; it was augmented by 2.1 microM palmitoyl carnitine. The leukocyte response induced by another putative activator of PKC, 1,2-isopropylidene-3-decanoyl-sn-glycerol, was also enhanced by 2.1 microM palmitoyl carnitine, slightly increased by staurosporine, TMB-8 and W-7 but not affected by calphostin C, H-7, K252a or Ro 31-7549, whereas the hyperosmolar mannitol-induced response was reduced by H-7, calphostin C, TMB-8 and W-7 and slightly augmented by staurosporine. Anti-IgE-induced histamine release was blocked by staurosporine and K252a and reduced by calphostin C, sphingosine, TMB-8 and W-7 but not affected by H-7, polymyxin B or retinal. It was enhanced by Ro 31-7549. In contrast, leukocyte histamine release induced by calcium ionophore A23187 or by ionomycin was blocked by retinal, TMB-8 and W-7 and reduced by calphostin C and palmitoyl carnitine but enhanced by H-7, staurosporine and polymyxin B; K252a and Ro 31-7549 did not affect such responses. Formyl-methionyl-leucyl-phenylalanine-triggered histamine release was barely affected by any agent used. Thus, the specific PKC inhibitor Ro 31-7549 selectively blocked 4 beta-phorbol 12-myristate 13-acetate-triggered leukocyte histamine release. These results imply that examined secretagogues trigger human leukocyte histamine release through partly separate pathways probably involving different kinase activities (PKC isozymes?). Moreover, the distinct effect patterns recorded for most purported PKC inhibitors imply a functional selectivity between these compounds.
Bergstrand
H
H
Preclinical Research Unit, Astra Draco AB, Lund, Sweden.
Lundquist
B
B
Karabelas
K
K
Michelsen
P
P
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D001491:Basophils / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D005995:Glyceryl Ethers / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008353:Mannitol / Q000494:pharmacology; D010172:Palmitoylcarnitine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D013110:Sphingosine / Q000494:pharmacology; D019311:Staurosporine; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D005995:Glyceryl Ethers; D007211:Indoles; D007546:Isoquinolines; D008301:Maleimides; D010879:Piperazines; D013449:Sulfonamides; D010172:Palmitoylcarnitine; D000001:Calcimycin; D008353:Mannitol; C058203:1,2-isopropylidene-3-decanoylglycerol; C017967:W 7; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D019311:Staurosporine; D011112:Polymyxin B; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate; C064755:Ro 31-7549