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Papers In Press, published online ahead of print September 19, 2002
Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033
Corresponding Author: yokomizo-tky{at}umin.ac.jp
Leukotriene B4 (LTB4) is a potent lipid mediator involved in host defense and inflammatory responses. It causes chemotaxis, generation of reactive oxygen species, and degranulation. However, only little is known of the molecular mechanisms how LTB4 induces these biological activities. To analyze the intracellular signaling pathways to mediate lysosomal enzyme release through the cloned LTB4 receptor (BLT1), we transfected BLT1 to rat basophilic leukemia cells (RBL-2H3). LTB4 dose- dependently released b-hexosaminidase, and the release was mostly inhibited when the cells were pretreated with pertussis toxin, indicating that the degranulation is mediated by Gi- proteins. LTB4 activated phosphatidylinositol 3-kinase (PI3-K) through Gi, and inhibition of PI3-K by wortmannin or LY290042 inhibited degranulation. Granulocytes from PI3-K g deficient mice showed reduced LTB4-iduced degranulation, suggesting that this isozyme of PI3-K is involved in the degranulation. LTB4 also caused Ca release from intracellular stores and Ca influx from the outside milieu through Gi, but only the Ca influx is critical for the lysosomal enzyme release. Ca influx and PI3-K activation are both downstream events of Gi, as they were inhibited by pertussis toxin. These two events are in essence independent each other, because Ca depletion did not affect PI3-K, and inhibition of PI3-K did not attenuate Ca influx significantly. Thus, our results have clearly shown that LTB4 binds BLT1 and activates Gi-like protein, and both PI3-K g activation and a sustained Ca elevation by Ca influx are necessary for enzyme release in these cells.
J. Biol. Chem, 10.1074/jbc.M208051200
Submitted on August 7, 2002
Revised on September 18, 2002
Accepted on September 19, 2002
Requirement of phosphatidylinositol 3-kinase-activation and Ca influx for leukotriene B4-induced enzyme release
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