Tumor necrosis factor-alpha autoregulates interleukin-6 synthesis via activation of protein kinase C - Function of sphingosine 1-phosphate and phosphatidylcholine-specific phospholipase C

被引:54
作者
Kozawa, O
Suzuki, A
Kaida, T
Tokuda, H
Uematsu, T
机构
[1] NAGOYA UNIV, SCH MED, DEPT INTERNAL MED 1, NAGOYA, AICHI 466, JAPAN
[2] CHUBA NATL HOSP, NATL INST LONGEV SCI, DEPT INTERNAL MED, AICHI 474, JAPAN
关键词
D O I
10.1074/jbc.272.40.25099
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We investigated the mechanism of interleukin-6 (IL-6) synthesis induced by tumor necrosis factor-alpha (TNF) in osteoblast-like MC3T3-E1 cells. TNF stimulated the synthesis of IL-6 dose dependently in the range between 1 and 30 ng/ml. Staurosporine and calphostin C, inhibitors of protein kinase C (PKC), significantly enhanced the TNF-induced synthesis of IL-6. 1-Oleoyl-2-acetylglycerol, a specific activator of PKC, inhibited the TNF-induced IL-6 synthesis. The stimulative effect of TNF was markedly increased in the PKC down-regulated cells, TNF produced diacylglycerol. TNF had little effect on the formation of inositol phosphates and choline, On the contrary, TNF significantly stimulated the formation of phosphocholine dose dependently. D-609, an inhibitor of phosphatidylcholine-specific phospholipase C, suppressed the TNF-induced diacylglycerol production, The TNF-induced IL-6 synthesis was significantly enhanced by D-609, TNF induced sphingomyelin hydrolysis. Neither C-2-ceramide nor sphingosine but sphingosine 1-phosphate significantly stimulated the synthesis of IL-6. PKC down-regulation amplified the IL-6 synthesis by sphingosine 1-phosphate. These results strongly suggest that sphingosine 1-phosphate may act as a second messenger for TNF-induced IL-6 synthesis and that TNF autoregulates IL-6 synthesis due to PKC activation via phosphatidylcholine-specific phospholipase C in osteoblast-like cells.
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页码:25099 / 25104
页数:6
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