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Lipoxygenase metabolites as mediators of UTP-induced intracellular acidification in mouse RAW 264.7 macrophages.

Abstract：

:In previous studies, we have shown that mouse RAW 264.7 macrophages possess pyrimidinoceptors, coupled to a phosphoinositide-specific phospholipase C, with a higher specificity for UTP than for ATP. In the current study, we explored the mechanism involved in the UTP-induced intracellular acidification seen in this cell line. UTP (30 microM) caused a reversible pHi decrease of 0.16 +/- 0.01 unit; this effect was not influenced by the removal of extracellular Cl- or Na+ ions or by pretreatment with 5-(N-ethyl-N-isopropyl)-amiloride (10 microM), 5-nitro-2-(3-phenylpropylamino)benzoic acid (100 microM), staurosporine (1 microM), or Ro 31-8220 (1 microM) but was completely abolished by the removal of extracellular Ca2+. UTP (30 microM), thapsigargin (1 microM), and ionomycin (1 microM) each induced a similar extent of external Ca2+-dependent acidification with a similar time-dependency, but the effects were nonadditive. To further investigate the Ca2+-dependent mechanism, we studied the involvement of arachidonic acid (AA) and eicosanoid metabolites. The addition of AA (10 microM) but not arachidic acid (100 microM) produced a reduction in pHi. UTP, thapsigargin, and ionomycin induced Ca2+-dependent AA release. Furthermore, 4-bromo-phenacyl bromide [30 microM, a phospholipase A2 (PLA2) inhibitor-, nordihydroguaiaretic acid (50 microM, a lipoxygenase inhibitor), and MK-886 (10 microM, a 5-lipoxygenase-activating protein inhibitor) abolished the UTP- or ionomycin-induced responses, whereas indomethacin (30 microM, a cyclooxygenase inhibitor) and baicalein (10 microM, a selective 12-lipoxygenase inhibitor) had no effect. MAFP (a cPLA2 inhibitor) and REV 5901 (a 5-lipoxygenase inhibitor as well as a competitive antagonist of peptide leukotrienes), but not RHC 80267 (a diacylglycerol lipase inhibitor), also inhibited the UTP-induced response. In contrast, the pHi response to AA was unaffected by the presence of 4-bromo-phenacyl bromide or the removal of extracellular Ca2+ ions but abolished by addition of NDGA. Exogenous 5-hydroperoxyeicosatetraenoic acid (2 microM) also produced marked acidification, and UTP and ionomycin both induced peptide leukotriene formation. In conclusion, this is the first report indicating that lipoxygenase metabolites act as mediators of the Ca2+-dependent acidification seen in macrophages in response to UTP or ionomycin via activation of cPLA2 and AA release.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Lin WW,Chang SH,Wu ML

doi

10.1124/mol.53.2.313

subject

Has Abstract

pub_date

1998-02-01 00:00:00

pages

313-21

issue

2

eissn

0026-895X

issn

1521-0111

journal_volume

53

pub_type

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