Lipoxin A4 antagonizes the mitogenic effects of leukotriene D4 in human renal mesangial cells: Differential activation of MAP kinases through distinct receptors

Blaithin McMahon, Catherine Stenson, Fiona McPhillips, Aine Fanning, Hugh R. Brady, Catherine Godson

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The lipoxygenase-derived eicosanoids leukotrienes and lipoxins are well defined regulators of hemeodynamics and leukocyte recruitment in inflammatory conditions. Here, we describe a novel bioaction of lipoxin A4 (LXA4), namely inhibition of leukotriene D4 (LTD4)-induced human renal mesangial cell proliferation, and investigate the signal transduction mechanisms involved. LXA4 blocked LTD4-stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity in parallel to inhibition of LTD4-induced mesangial cell proliferation. Screening of a human mesangial cell cDNA library revealed expression of the recently described cys-leukotriene1/LTD4 receptor. LTD4-induced mesangial cell proliferation required both extracellular-related signal regulated kinase (erk) and PI 3-kinase activation and may involve platelet-derived growth factor receptor transactivation. LTD4-stimulated the MAP kinases erk and p38 via a pertussis toxin (PTX)-sensitive pathway dependent on PI 3-kinase and protein kinase C activation. On screening a cDNA library, mesangial cells were found to express the previously described LXA4 receptor. In contrast to LTD4, LXA4 showed differential activation of erk and p38. LXA4 activation of erk was insensitive to PTX and PI 3-kinase inhibition, whereas LXA4 activation of p38 was sensitive to PTX and could be blocked by the LTD4 receptor antagonist SKF 104353. These data suggest that LXA4 stimulation of the MAP kinase superfamily involves two distinct receptors: one shared with LTD4 and coupled to a PTX-sensitive G protein (G(i)) and a second coupled via an alternative G protein, such as G(q) or G12, to erk activation. These data expand on the spectrum of LXA4 bioactions within an inflammatory milieu.

Original languageEnglish (US)
Pages (from-to)27566-27575
Number of pages10
JournalJournal of Biological Chemistry
Issue number36
StatePublished - Sep 8 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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