Lipoxin, leukotriene, and PDGF receptors cross-talk to regulate mesangial cell proliferation.

Abstract

The lipoxygenase-derived leukotrienes (LTs) are important proinflammatory lipid mediators. Lipoxins (LXs), more recently described lipoxygenase products, modulate many proinflammatory actions of LTs and have impressive proresolution properties. Mesangial cell (MC) proliferation is a central event in the pathogenesis of glomerulonephritis. LTD4-induced proliferation of mesangial cells is modulated by LXA4. Here, we demonstrate that LXA4 inhibits PDGF- and LTD4-stimulated proliferation through modulation of platelet-derived growth factor receptor beta (PDGFRbeta) activation. Specifically, we demonstrate that LTD4 transactivates the PDGFRbeta, a process associated with c-src recruitment and ras activation. We demonstrate expression of cysLT1 and cysLT2 receptors in MCs. LTD4-induced c-src activation was insensitive to pertussis toxin and the cysLT1 receptor antagonist Zafirlukast but was blocked by the nonselective antagonist Pobilukast. We show that LXA4 inhibits LTD4-stimulated activation of the PDGFRbeta and that LXA4 modulates PDGF-BB-stimulated tyrosine phosphorylation of the PDGFRb and subsequent mitogenic events. Furthermore, expression of recombinant LXA4 receptor (ALXR) in CHOK1 cells was associated with an attenuation of serum-stimulated proliferation. These data demonstrate that LXA4 receptor (ALXR) activation is accompanied by antimitogenic effects coupled with inactivation of growth factor receptors, highlighting the complex cross-talk between G protein-coupled receptors and receptor tyrosine kinases in an inflammatory milieu. These data elaborate on the profile of cell signaling events that underpin the anti-inflammatory and proresolution bioactions of LX.