7-Ketocholesterol upregulates interleukin-6 via mechanisms that are distinct from those of tumor necrosis factor-alpha, in vascular smooth muscle cells.
This study investigated the effects of 7-ketocholesterol on interleukin (IL)-6 expression in vascular smooth muscle cells (VSMC). Among the 7 IL examined, only IL-6 transcript was increased by 7-ketocholesterol treatment in human aorta smooth muscle cells. IL-6 transcripts increased up to 24 h after treatment with 7-ketocholesterol, and this effect was profoundly repressed by treatment with p38 MAPK inhibitors and to a lesser extent JNK inhibitors. 7alpha-Hydroxycholesterol, 27-hydroxycholesterol or cholesterol, however, did not induce IL-6 expression. Mechanisms of IL-6 induction by 7-ketocholesterol were investigated in comparison with tumor necrosis factor (TNF)-alpha. Whereas TNF-alpha activated IL-6 promoter, which was impaired by p38 MAPK inhibitors or by mutation in the NF-kappaB-binding site within the promoter region, 7-ketocholesterol did not affect IL-6 promoter activity. Instead, this oxysterol slowed degradation of IL-6 mRNA and increased the amount of cytoplasmic HuR. 7-ketocholesterol significantly increased the amount of intracellular IL-6 protein in the presence of brefeldin A. 7-Ketocholesterol also enhanced IL-6 release from VSMC. IL-6 release by 7-ketocholesterol, although significant, was not as remarkable as that induced by TNF-alpha. These data suggest that 7-ketocholesterol upregulates IL-6 via mechanisms distinct from TNF-alpha and contributes to the intra- and extracellular IL-6 deposits within the vasculature.
Department of Thoracic and Cardiovascular Surgery, Pusan National University, Busan, Korea.
Si-Chan
SC
Sung
Koanhoi
K
Kim
Kyeong-Ah
KA
Lee
Kyung-Ha
KH
Choi
Sun-Mi
SM
Kim
Yong-Hae
YH
Son
Yu-Seok
YS
Moon
Seong-Kug
SK
Eo
Byung-Yong
BY
Rhim
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D020126:Brefeldin A / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D051959:ELAV Proteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D007653:Ketocholesterols / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
D000873:Anthracenes; D022762:CCAAT-Enhancer-Binding Proteins; D051959:ELAV Proteins; D007093:Imidazoles; D015850:Interleukin-6; D007653:Ketocholesterols; D016328:NF-kappa B; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; C432165:pyrazolanthrone; D020126:Brefeldin A; C003001:7-ketocholesterol; C093642:SB 203580