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

doi:10.1074/jbc.m001015200

Abstract

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 A(4) (LXA(4)), namely inhibition of leukotriene D(4) (LTD(4))-induced human renal mesangial cell proliferation, and investigate the signal transduction mechanisms involved. LXA(4) blocked LTD(4)-stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity in parallel to inhibition of LTD(4)-induced mesangial cell proliferation. Screening of a human mesangial cell cDNA library revealed expression of the recently described cys-leukotriene(1)/LTD(4) receptor. LTD(4)-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. LTD(4)-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 LXA(4) receptor. In contrast to LTD(4), LXA(4) showed differential activation of erk and p38. LXA(4) activation of erk was insensitive to PTX and PI 3-kinase inhibition, whereas LXA(4) activation of p38 was sensitive to PTX and could be blocked by the LTD(4) receptor antagonist SKF 104353. These data suggest that LXA(4) stimulation of the MAP kinase superfamily involves two distinct receptors: one shared with LTD(4) and coupled to a PTX-sensitive G protein (G(i)) and a second coupled via an alternative G protein, such as G(q) or G(12), to erk activation. These data expand on the spectrum of LXA(4) bioactions within an inflammatory milieu.

Highlights

The lipoxygenase-derived eicosanoids leukotrienes and lipoxins are well defined regulators of hemeodynamics and leukocyte recruitment in inflammatory conditions
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
These data suggest that LXA4 stimulation of the MAP kinase superfamily involves two distinct receptors: one shared with LTD4 and coupled to a pertussis toxin (PTX)-sensitive G protein (Gi) and a second coupled via an alternative G protein, such as Gq or G12, to erk activation

Summary

Introduction

The lipoxygenase-derived eicosanoids leukotrienes and lipoxins are well defined regulators of hemeodynamics and leukocyte recruitment in inflammatory conditions. 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. 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. 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 (Gi) and a second coupled via an alternative G protein, such as Gq or G12, to erk activation These data expand on the spectrum of LXA4 bioactions within an inflammatory milieu. Activation of the PI 3-kinase family of lipid kinases regulates multiple cell functions, including proliferation

Methods

Results

Conclusion