Lipoxin A4 inhibits connective tissue growth factor-induced production of chemokines in rat mesangial cells

Connective tissue growth factor (CTGF) is involved in mitogenesis, matrix production, and chemotaxis in mesenchymal cells. The effects of CTGF on the production of chemokines remain unclear. The present studies investigate the regulatory role of CTGF in the production of fractalkine, monocyte chemoattractant protein-1 (MCP-1), and RANTES (regulated upon activation, normal T cell expressed and secreted) in cultured mesangial cells of rats, and the modulatory effects of lipoxin A4 (LXA4) on actions of CTGF. CTGF enhanced the mRNA expression and protein release of fractalkine, MCP-1, and RANTES, the expression of phospho (P)-p42/44 mitogen-activated protein kinase (MAPK), P-phosphoinositide 3-kinase (PI3-K), P-Akt, and activity of nuclear factor-κB (NF-κB) in mesangial cells. P-p42/44 MAPK blockade inhibited the CTGF-induced expression of P-p42/44 MAPK but not NF-κB, and partially decreased the levels of the above chemokines in supernatants. P-PI3-K blockade downregulated the CTGF-stimulated expression of P-PI3-K, P-Akt, and NF-κB but not P-p42/44 MAPK, and partially decreased the release of the above chemokines. NF-κB blockade abrogated the CTGF-activated NF-κB and partially decreased the secretion of the above chemokines. LXA4 dose-dependently inhibited the CTGF-stimulated mRNA expression and protein release of the above chemokines, and the expression of P-p42/44MAPK, P-PI3-K, P-Akt, and NF-κB. In conclusion, these results demonstrate that CTGF induces production of fractalkine, MCP-1, and RANTES via the p42/44 MAPK-, PI3-K/Akt-, and NF-κB-dependent signal pathway, and LXA4 downregulates the above effects of CTGF on rat mesangial cells.