Sphingomyelin synthase 2 deficiency attenuates NFkappaB activation.
BACKGROUND
NFkappaB has long been regarded as a proatherogenic factor, mainly because of its regulation of many of the proinflammatory genes linked to atherosclerosis. Metabolism of sphingomyelin (SM) has been suggested to affect NFkappaB activation, but the mechanism is largely unknown. SMS2 regulates SM levels in cell plasma membrane and lipid rafts and has a potential to regulate NFkappaB activation.


RESULTS
To investigate the role of SMS2 in NFkappaB activation we used macrophages from SMS2 knockout (KO) mice and SMS2 siRNA-treated HEK 293 cells. We found that NFkappaB activation and its target gene expression are attenuated in macrophages from SMS2 KO mice in response to lipopolysaccharide (LPS) stimulation and in SMS2 siRNA- treated HEK 293 cells after tumor necrosis factor (TNF)-alpha simulation. In line with attenuated NFkappaB activation, we found that SMS2 deficiency substantially diminished the abundance of toll like receptor 4 (TLR4)-MD2 complex levels on the surface of macrophages after LPS stimulation, and SMS2 siRNA treatment reduced TNF-alpha-stimulated lipid raft recruitment of TNF receptor-1 (TNFR1) in HEK293 cells. SMS2 deficiency decreased the relative amounts of SM and diacylglycerol (DAG) and increased ceramide, suggesting multiple mechanisms for the decrease in NFkappaB activation.


CONCLUSIONS
SMS2 is a modulator of NFkappaB activation, and thus it could play an important role in NFkappaB-mediated proatherogenic process.
Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
Tiruneh K
TK
Hailemariam
Chongmin
C
Huan
Jing
J
Liu
Zhiqiang
Z
Li
Christopher
C
Roman
Michael
M
Kalbfeisch
Hai H
HH
Bui
David A
DA
Peake
Ming-Shang
MS
Kuo
Guoqing
G
Cao
Raj
R
Wadgaonkar
Xian-Cheng
XC
Jiang
D000818:Animals; D002460:Cell Line; D006801:Humans; D008264:Macrophages; D021962:Membrane Microdomains / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D013109:Sphingomyelins / Q000378:metabolism*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000172:deficiency / Q000502:physiology*
D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D013109:Sphingomyelins; C455440:SGMS1 protein, human; D017855:Transferases (Other Substituted Phosphate Groups); C019863:ceramide cholinephosphotransferase