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

J Pharmacol Exp Ther. 1991 Sep;258(3):824-9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkaloids / pharmacology
  • Antibodies, Anti-Idiotypic / pharmacology
  • Arachidonic Acid
  • Arachidonic Acids / metabolism
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / enzymology
  • Calcimycin / pharmacology
  • Dose-Response Relationship, Drug
  • Histamine Release / drug effects
  • Humans
  • Immunoglobulin E / immunology
  • Immunoglobulin E / pharmacology
  • Immunoglobulin E / physiology*
  • Lung / cytology
  • Lung / drug effects
  • Lung / enzymology*
  • Mast Cells / drug effects
  • Mast Cells / enzymology*
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C / metabolism
  • Protein Kinase C / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Skin / cytology
  • Skin / drug effects
  • Skin / enzymology*
  • Staurosporine
  • Tetradecanoylphorbol Acetate / pharmacology
  • Time Factors

Substances

  • Alkaloids
  • Antibodies, Anti-Idiotypic
  • Arachidonic Acids
  • anti-IgE antibodies
  • Arachidonic Acid
  • Immunoglobulin E
  • Calcimycin
  • Protein Kinase C
  • Staurosporine
  • Tetradecanoylphorbol Acetate