Differential effects of sphingomyelin hydrolysis and resynthesis on the activation of NF-κB in normal and SV40-transformed human fibroblasts

被引:58
作者
Luberto, C
Yoo, DS
Suidan, HS
Bartoli, GM
Hannun, YA
机构
[1] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA
[2] Duke Univ, Med Ctr, Dept Med, Div Gastroenterol, Durham, NC 27710 USA
[3] Univ Cattolica Sacro Cuore, Inst Gen Pathol, I-00168 Rome, Italy
[4] Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy
关键词
D O I
10.1074/jbc.275.19.14760
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
The precise role of ceramide in NF-kappa B signaling remains unclear. The recent observation of differential sphingomyelin synthase (SMS) activity in normal (low SMS) versus SV40-transformed thigh SMS) WI38 human lung fibroblasts provides an opportunity to assess the involvement of ceramide and SMS in NF-kappa B activation. Treatment of normal WI38 fibroblasts with bacterial sphingomyelinase resulted in a 4-fold elevation of ceramide and blocked NF-kappa B activation by serum stimulation. Such inhibition was not observed in SV40-transformed fibroblasts. Under regular growth conditions, after sphingomyelinase was washed out, normal WI38 did not show SM re-synthesis nor NF-kappa B activation. In SV40-WI38, on the other hand, sphingomyelinase washout induced resynthesis of SM due to the action of SMS on ceramide generated at the plasma membrane. NF-kappa B activation correlated with SM resynthesis. This activation was abrogated by D609, which inhibited SM resynthesis but not the initial formation of ceramide. The differential activity of SMS may explain the effects of ceramide in NF-kappa B signaling: in the absence of significant SIMS activity, ceramide inhibits NF-kappa B, whereas with high SMS, the conversion of the ceramide signal to a diacylglycerol signal by the action of SMS stimulates NF-kappa B. These results also suggest a role for SMS in regulating NF-kappa B.
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页码:14760 / 14766
页数:7
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