Substance P activates the release of histamine from human skin mast cells through a pertussis toxin-sensitive and protein kinase C-dependent mechanism.
Using pharmacologic agents, we explored the mechanism by which a potent neuropeptide, substance P, induces the secretion of histamine from human skin mast cells and compared their effects on substance P-induced histamine release to the secretion activated by anti-IgE. Histamine release from human cutaneous mast cells induced by substance P was inhibited by the Ge-protein inhibitor pertussis toxin that, in turn, did not affect the IgE-mediated secretion. Similarly to anti-IgE, two activators of protein kinase C, tetradecanoylphorbol acetate (TPA) and bryostatin 1, significantly inhibited the substance P-induced response. In contrast, drugs that enhance intracellular levels of cAMP, an inhibitor of protein kinases, genistein, and a protease inhibitor, AEBSF, did not affect substance P-induced histamine secretion, whereas these compounds significantly reduced the response initiated by anti-IgE. Our data demonstrate that substance P activates human cutaneous mast cells by acting on G proteins and protein kinase C. Our results also suggest that the biochemical pathways underlying mast cell activation by substance P and anti-IgE are to a great extent unrelated.
Columbo
M
M
Johns Hopkins Asthma & Allergy Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Horowitz
E M
EM
Kagey-Sobotka
A
A
Lichtenstein
L M
LM
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D054713:Bryostatins; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D019833:Genistein; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D007073:Immunoglobulin E / Q000378:metabolism; D066298:In Vitro Techniques; D007529:Isoflavones / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology* / Q000502:physiology; D037342:Pertussis Toxin; D011480:Protease Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000276:immunology*; D012879:Skin Physiological Phenomena; D013373:Substance P / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000888:Antibodies, Anti-Idiotypic; D054713:Bryostatins; D007529:Isoflavones; D007783:Lactones; D018942:Macrolides; D011480:Protease Inhibitors; D013450:Sulfones; D010566:Virulence Factors, Bordetella; D013373:Substance P; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D007073:Immunoglobulin E; C046785:bryostatin 1; D019833:Genistein; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate; D015056:1-Methyl-3-isobutylxanthine