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

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.