Akt1/p27~(kip1) Pathway Mediates Inhibition of LXA_4 on TNF-α- induced Proliferation of Rat Mesangial Cells

摘要

Objective: To examine whether lipoxin A_4 ( LXA_4 ) has an inhibitory effect on tumor necrosis factor- α (TNF-α) -induced proliferation of glomerular mesangial cells of rat, and explore the molecular mechanisms of signal pathway in LXA_4 actions. Methods: Glomerular mesangial cells of rat were cultured and treated with TNF-α(10 ng/ml), with or without preincubation with LXA_4 at different concentrations. Cell proliferation was evaluated by monotetrazoli-um (MTT) colorimetric assay. The expression of cyclin E mRNA was measured by RT-PCR. Phosphorylated Akt1 (Thr308) and p27~(kip1) were analyzed by Western blotting. Results: TNF-α- stimulated proliferation of mesangial cells was inhibited by LXA_4 in a dose- dependent manner. The marked increments in cyclin E mRNA expression induced by TNF-α during proliferation of mesangial cells were down- regulated by LXA_4. Threonine phosphorylated Akt1 proteins at 308 site stimulated by TNF-α was reduced by LXA_4. TNF-α- induced decrements in expression of p27~(kip1) proteins was ameliorated by LXA_4 in a dose- dependent manner. Conclusion: TNF-?- induced proliferation of rat mesangial cells can be inhibited by TXA_4 through the mechanism of Akt_1/p27~(kip1) pathway- dependent signal transduction.