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 A(4) (LXA(4)) 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-kappaB (NF-kappaB) in mesangial cells. P-p42/44 MAPK blockade inhibited the CTGF-induced expression of P-p42/44 MAPK but not NF-kappaB, 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-kappaB but not P-p42/44 MAPK, and partially decreased the release of the above chemokines. NF-kappaB blockade abrogated the CTGF-activated NF-kappaB and partially decreased the secretion of the above chemokines. LXA(4) 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-kappaB. 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-kappaB-dependent signal pathway, and LXA(4) downregulates the above effects of CTGF on rat mesangial cells.
Wu
S-H
SH
Department of Pediatrics, Central Laboratory, The First Affiliated Hospital of Nanjing Medical University, Jiangsu, People's Republic of China. kad-yc@163.com
Wu
X-H
XH
Lu
C
C
Dong
L
L
Zhou
G-P
GP
Chen
Z-Q
ZQ
D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054428:Chemokine CX3CL1; D018925:Chemokines / Q000096:biosynthesis*; D020523:Chemokines, CX3C / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor; D004247:DNA / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors*; D036341:Intercellular Signaling Peptides and Proteins; D044045:Lipoxins / Q000494:pharmacology*; D008565:Membrane Proteins / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats
D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054428:Chemokine CX3CL1; D018925:Chemokines; D020523:Chemokines, CX3C; D055513:Connective Tissue Growth Factor; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D044045:Lipoxins; D008565:Membrane Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C526316:CCN2 protein, rat; C515540:Cx3cl1 protein, rat; C040527:lipoxin A4