Na+/H+ exchange modulates the production of leukotriene B4 by human neutrophils

Biochemical Journal - Tập 257 Số 3 - Trang 751-758 - 1989
Mitsuhiko Osaki1, Hidetoshi Sumimoto2, Koichiro Takeshige2, Edward J. Cragoe3, Yuta Hori1, Shigeki Minakami2
1Department of Dermatology, Kyushu University School of Medicine, Fukuoka, 812, Japan
2Department of Biochemistry, Kyushu University School of Medicine, Fukuoka 812 Japan
3Department of Biochemistry, Kyushu University School of Medicine, Fukuoka 2211 Oak Terrace Drive, Lansdale, PA 19446, U.S.A.

Tóm tắt

Human neutrophils produce various compounds of the 5-lipoxygenase pathway, including (5S)-hydroxyeicosatetraenoic acid, leukotriene B4, its 6-trans isomers and omega-oxidation metabolites of LTB4, when the cells are stimulated with the Ca2+ ionophore A23187. The elevation in the extracellular pH (pHo) facilitated the cytoplasmic alkalinization induced by the ionophore as determined fluorometrically using 2',7'-bis(carboxyethyl)carboxyfluorescein and enhanced the production of all the 5-lipoxygenase metabolites. The production decreased when the alkalinization was blocked by the decrease in the pHo, the removal of the extracellular Na+ or the addition of specific inhibitors of the Na+/H+ exchange, such as 5-(NN-hexamethylene)amiloride, 5-(N-methyl-N-isobutyl)amiloride and 5-(N-ethyl-N-isopropyl)amiloride. The alkalinization of the cytoplasm with methylamine completely restored the production suppressed by the removal of Na+ from the medium. These findings suggest that the change in the cytoplasmic pH (pHi) mediated by the Na+/H+ exchange regulates the production of the lipoxygenase metabolites. The site of the metabolism controlled by the pHi change seemed to be the 5-lipoxygenase, because the production of all the metabolites decreased in parallel and the release of [3H]arachidonic acid from the neutrophils in response to the ionophore was not affected by the pHi change. Furthermore, the production of the 5-lipoxygenase metabolites stimulated by A23187 with or without exogenous arachidonic acid showed a similar pHo-dependence and the production induced by N-formylmethionyl-leucylphenylalanine (chemotactic peptide) with exogenous arachidonic acid also decreased when the cytoplasmic alkalinization was inhibited.

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Biochemical Journal

Tập 257 Số 3

751-758

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