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Lipoxin, leukotriene, and PDGF receptors cross‐talk to regulate mesangial cell proliferation
Author(s) -
Mc Mahon Blaithin,
Mitchell Derick,
Shattock Richard,
Martin Finian,
Brady Hugh R.,
Godson Catherine
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0416fje
Subject(s) - platelet derived growth factor receptor , microbiology and biotechnology , mesangial cell , tyrosine phosphorylation , receptor , proinflammatory cytokine , growth factor , tyrosine kinase , chemistry , signal transduction , cell growth , cancer research , biology , endocrinology , inflammation , biochemistry , immunology , kidney
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. LTD 4 ‐induced proliferation of mesangial cells is modulated by LXA 4 . Here, we demonstrate that LXA 4 inhibits PDGF‐ and LTD 4 ‐stimulated proliferation through modulation of platelet‐derived growth factor receptor β (PDGFRβ) activation. Specifically, we demonstrate that LTD 4 transactivates the PDGFRβ, a process associated with c‐src recruitment and ras activation. We demonstrate expression of cysLT 1 and cysLT 2 receptors in MCs. LTD 4 ‐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 LTD 4 ‐stimulated activation of the PDGFRβ and that LXA 4 modulates PDGF‐BB‐stimulated tyrosine phosphorylation of the PDGFRβ 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.