Protein kinase C modulates immunoglobulin E-mediated activation of human mast cells from lung and skin. I. Pharmacologic inhibition

WA Massey, VL Cohan, DW MacGlashan , SW Gittlen, A Kagey-Sobotka, LM Lichtenstein and JA Warner

Division of Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland.

It is widely appreciated that protein kinase C (PKC) is activated in a variety of secretory cells after stimulation. By using two complementary pharmacologic approaches, we have investigated the role of PKC in immunoglobulin E (IgE)-mediated secretion from human lung, bronchoalveolar lavage and skin mast cells. We examined the effect of the PKC inhibitor, staurosporine, on goat anti-human IgE-induced mediator release. In lung mast cells, the IC50 for staurosporine on histamine release was 2.8 +/- 1.4 nM (n = 9). The drug was slightly more potent in skin mast cells where the IC50 was 0.64 +/- 2.0 nM (n = 6), but staurosporine had no effect on the IgE-mediated release of histamine from bronchoalveolar lavage mast cells. Mast cells were also incubated overnight with the phorbol ester 12-O-tetradecanoylphorbol-13- acetate (TPA) to down regulate PKC and the response to goat anti-human IgE was measured. Prolonged exposure to 100 ng/ml of TPA reduced IgE- mediated histamine release from 28 +/- 6 to 6 +/- 1% in the skin mast cells whereas similar treatment only reduced the response of lung mast cells from 36 +/- 5 to 26 +/- 6%. Despite using agents which act by different mechanisms, short-term inhibition with staurosporine and long- term treatment with TPA, we obtained consistent results which suggest that PKC is playing a prorelease role in IgE-mediated signaling. Our results also suggest that skin and lung mast cells are more sensitive to PKC down-regulation than bronchoalveolar mast cells. This heterogeneity between human mast cells at the level of PKC regulation of cell activation is previously undescribed.

Volume 258, Issue 3, pp. 824-829, 09/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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