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

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 LXA(4). Here, we demonstrate that LXA(4) 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 cysLT(1) and cysLT(2) receptors in MCs. LTD4-induced c-src activation was insensitive to pertussis toxin and the cysLT(1) receptor antagonist Zafirlukast but was blocked by the nonselective antagonist Pobilukast. We show that LXA(4) inhibits LTD4-stimulated activation of the PDGFRbeta and that LXA(4) modulates PDGF-BB-stimulated tyrosine phosphorylation of the PDGFRbeta and subsequent mitogenic events. Furthermore, expression of recombinant LXA(4) receptor (ALXR) in CHOK1 cells was associated with an attenuation of serum-stimulated proliferation. These data demonstrate that LXA(4) 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.