TY - JOUR
T1 - Ceramide-induced enhancement of secretory phospholipase A2 expression via generation of reactive oxygen species in tumor necrosis factor-α-stimulated mesangial cells
AU - Kitatani, Kazuyuki
AU - Akiba, Satoshi
AU - Sato, Takashi
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Scientific Research from, and by the Frontier Research Program of, The Ministry of Education, Science, Sports and Culture of Japan.
PY - 2004/8
Y1 - 2004/8
N2 - Since prostanoids such as prostaglandin E2 play a pivotal role in modulating renal function, we investigated the involvement of ceramide in expression of secretory phospholipase A2 (sPLA2) and cyclooxygenase-2 (COX-2) in tumor necrosis factor-α (TNF-α)- stimulated mesangial cells. TNF-α stimulation increased ceramide generation in parallel with a decrease in sphingomyelin. Pretreatment with exogenous sphingomyelinase (SMase) dose-dependently enhanced TNF-α-stimulated increases in COX-2 protein and sPLA2 activity. SMase also augmented TNF-α-mediated nuclear factor κB (NF-κB) activation. N-acetylcysteine (NAC), an antioxidant, completely inhibited the SMase-induced increase in sPLA2 activity, whereas NAC inhibited partially the activity stimulated with TNF-α alone. Under the conditions, NAC completely inhibited reactive oxygen species (ROS) production induced by SMase followed by TNF-α. These results suggest that ceramide elicits up-regulation of NF-κB through ROS production, which, in turn, leads to stimulation of COX-2 and sPLA2 expression. Therefore, ceramide may be implicated in the pathogenesis of renal abnormalities.
AB - Since prostanoids such as prostaglandin E2 play a pivotal role in modulating renal function, we investigated the involvement of ceramide in expression of secretory phospholipase A2 (sPLA2) and cyclooxygenase-2 (COX-2) in tumor necrosis factor-α (TNF-α)- stimulated mesangial cells. TNF-α stimulation increased ceramide generation in parallel with a decrease in sphingomyelin. Pretreatment with exogenous sphingomyelinase (SMase) dose-dependently enhanced TNF-α-stimulated increases in COX-2 protein and sPLA2 activity. SMase also augmented TNF-α-mediated nuclear factor κB (NF-κB) activation. N-acetylcysteine (NAC), an antioxidant, completely inhibited the SMase-induced increase in sPLA2 activity, whereas NAC inhibited partially the activity stimulated with TNF-α alone. Under the conditions, NAC completely inhibited reactive oxygen species (ROS) production induced by SMase followed by TNF-α. These results suggest that ceramide elicits up-regulation of NF-κB through ROS production, which, in turn, leads to stimulation of COX-2 and sPLA2 expression. Therefore, ceramide may be implicated in the pathogenesis of renal abnormalities.
KW - Ceramide
KW - Cyclooxygenase-2
KW - Mesangial cells
KW - Nuclear factor κB
KW - Reactive oxygen species
KW - Secretory phospholipase A
KW - Tumor necrosis factor-α
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U2 - 10.1016/j.cellsig.2004.02.003
DO - 10.1016/j.cellsig.2004.02.003
M3 - Article
C2 - 15157676
AN - SCOPUS:2442539389
VL - 16
SP - 967
EP - 974
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
IS - 8
ER -