The phosphatidylinositol 3-kinase inhibitor wortmannin blocks mast cell exocytosis but not IL-6 production

Phosphatidylinositol 3-kinase (PI3-kinase) activity has been shown to be important in cellular signaling via receptors associated with tyrosine kinases and receptors coupled to small or heterotrimeric G proteins. The importance of this activity in mast cell degranulation, leukotriene C4 generation,...

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Bibliographic Details
Published in:	The Journal of immunology (1950) Vol. 156; no. 5; pp. 1942 - 1945
Main Authors:	Marquardt, DL, Alongi, JL, Walker, LL
Format:	Journal Article
Language:	English
Published:	United States Am Assoc Immnol 01-03-1996
Subjects:	Androstadienes - pharmacology Animals Arachidonic Acid - metabolism Bone Marrow Cells Cell Degranulation - drug effects Exocytosis - drug effects Interleukin-6 - biosynthesis Mast Cells - drug effects Mast Cells - enzymology Mast Cells - ultrastructure Mice Mice, Inbred BALB C Phosphatidylinositol 3-Kinases Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
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Summary:	Phosphatidylinositol 3-kinase (PI3-kinase) activity has been shown to be important in cellular signaling via receptors associated with tyrosine kinases and receptors coupled to small or heterotrimeric G proteins. The importance of this activity in mast cell degranulation, leukotriene C4 generation, and IL-6 production was examined in mouse bone marrow-derived mast cells stimulated by high affinity IgE receptor cross-linking, direct influx of calcium, and/or adenosine receptor agonist exposure. Wortmannin, a fungal metabolite that at nanomolar concentrations inhibits PI3-kinase relatively specifically, blocked the release of granule-associated mast cell mediators independent of the secretory stimulus used. This inhibition was most prominent after a 2- to 5-min preincubation with wortmannin and was equally effective in cells additionally treated with exogenous N-ethylcarboxamidoadenosine to potentiate preformed mediator release. Mast cell production of leukotriene C4 20 min after activation or IL-6 16 h after activation was unaffected by up to 100 nM of wortmannin exposure. Mast cells preincubated with wortmannin failed to develop the classic electronmicroscopic evidence of granule swelling and fusion, increased membrane ruffling, or exocytosis upon Ag challenge. Activation of PI3-kinase appears to be critical for mast cell degranulation but is not required for arachidonic acid metabolism or cytokine production to occur. Furthermore, the inhibition of mast cell secretion by wortmannin is not stimulus specific but is evident for both IgE receptor cross-linking and direct calcium influx.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.156.5.1942