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J. Biol. Chem., Vol. 278, Issue 48, 48474-48484, November 28, 2003

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The Phospholipase C₁-dependent Pathway of FcRI-mediated Mast Cell Activation Is Regulated Independently of Phosphatidylinositol 3-Kinase^*

Christine Tkaczyk, Michael A. Beaven, Saskia M. Brachman¶||**, Dean D. Metcalfe, and Alasdair M. Gilfillan

From the Laboratory of Allergic Diseases, NIAID, Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, the ^¶Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, and the ^||Institut fuer Biochemie, Freie Universitaet Berlin, Berlin, Germany

Mast cell degranulation following FcRI aggregation is generally believed to be dependent on phosphatidylinositide 3-kinase (PI 3-kinase)-mediated phospholipase C (PLC) activation. Here we report evidence that the PLC₁-dependent pathway of FcRI-mediated activation of mast cells is independent of PI 3-kinase activation. In primary cultures of human mast cells, FcRI aggregation induced a rapid translocation and phosphorylation of PLC₁, and subsequent inositol trisphosphate (IP₃) production, which preceded PI 3-kinase-related signals. In addition, although PI 3-kinase-mediated responses were completely inhibited by wortmannin, even at high concentrations, this PI 3-kinase inhibitor had no effect on parameters of FcRI-mediated PLC activation, and had little effect on the initial increase in intracellular calcium levels that correlated with PLC activation. Wortmannin, however, did produce a partial (50%) concentration-dependent inhibition of FcRI-mediated degranulation in human mast cells and a partial inhibition of the later calcium response at higher concentrations. Further studies, conducted in mast cells derived from the bone marrow of mice deficient in the p85 and p85 subunits of PI 3-kinase, also revealed no defects in FcRI-mediated PLC₁ activation. These data are consistent with the conclusion that the PLC-dependent component of FcRI-mediated calcium flux leading to degranulation of mast cells is independent of PI 3-kinase. However, PI 3-kinase may contribute to the later phase of FcRI-mediated degranulation in human mast cells.

Received for publication, February 6, 2003 , and in revised form, September 12, 2003.

^* This work was supported in part by the NIAID, National Institutes of Health Intramural Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Supported by a fellowship from Boehringer Ingelheim Fonds.

To whom correspondence should be addressed: Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bldg. 10, Rm. 11C206, 10 Center Dr. MSC 1881, Bethesda, MD 20892-1881. Tel.: 301-496-8757; Fax: 301-480-8384; E-mail: agilfillan{at}niaid.nih.gov.

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