Low-density lipoprotein-induced expression of interleukin-6, a marker of human mesangial cell inflammation: effects of oxidation and modulation by lovastatin.
Low-density lipoprotein (LDL) may contribute to the pathogenesis of glomerulosclerosis by stimulating a mesangial cell inflammatory response. Interleukin-6 (IL-6) is a marker of active inflammation and ongoing glomerular injury. Therefore, we investigated the effects of native and oxidized LDL on human mesangial cell production of IL-6 and a possible modulation of this inflammatory response by lovastatin, which has been shown to ameliorate experimental glomerulosclerosis. Human mesangial cells were exposed for 6 or 24 h to culture medium containing either native LDL alone or a LDL mixture containing 5 or 20% oxidized LDL. We found that native LDL stimulated 6 h mRNA expression and secretion of IL-6. This effect was further enhanced, in a dose-related manner, when mesangial cells were exposed to increasing concentrations of oxidized LDL. Lovastatin markedly inhibited mesangial cell expression of IL-6 mRNA and reduced IL-6 secretion. The inhibitory effects of lovastatin were overridden at least partially by exogenous mevalonate. We conclude that LDL, and particularly oxidized LDL, might contribute to the pathogenesis of glomerular disease by modulating the inflammatory response of human mesangial cells, as assessed by the stimulation of IL-6 expression. Moreover, this inflammatory response can be prevented by lovastatin, providing a potential direct anti-inflammatory mechanism by which HMG-CoA reductase inhibitors may attenuate lipid-induced glomerular injury.
Massy
Z A
ZA
Division of Nephrology, Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA. massy@citi2.fr
Kim
Y
Y
Guijarro
C
C
Kasiske
B L
BL
Keane
W F
WF
O'Donnell
M P
MP
D001483:Base Sequence; D015415:Biomarkers; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D010084:Oxidation-Reduction
D015415:Biomarkers; D017931:DNA Primers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D015850:Interleukin-6; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D008148:Lovastatin