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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1519.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Sphingomyelin Synthase 2 Deficiency Attenuates NFB Activation

Tiruneh K. Hailemariam; Chongmin Huan; Jing Liu; Zhiqiang Li; Christopher Roman; Michael Kalbfeisch; Hai H. Bui; David A. Peake; Ming-Shang Kuo; Guoqing Cao; Raj Wadgaonkar; Xian-Cheng Jiang

From the Department of Anatomy and Cell Biology, Department of Microbiology and Immunology, Department of Medicine, State University of New York Downstate Medical Center (T.K.H., C.H., J.L., Z.L., C.R., R.W.), Brooklyn; and Lilly Research Laboratories (M.K., H.H.B., D.A.P., M.-S.K., G.C.), Eli Lilly & Company, Indianapolis, Ind.

Correspondence to Xian-Cheng Jiang, PhD, SUNY Downstate Medical Center, 450 Clarkson Ave, Box 5, Brooklyn, NY 11203. E-mail XJiang{at}downstate.edu or Raj Wadgaonkar, PhD, SUNY Downstate Medical Center. E-mail: rwadgaonker@downstate.edu

Background— NFB 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 NFB activation, but the mechanism is largely unknown. SMS2 regulates SM levels in cell plasma membrane and lipid rafts and has a potential to regulate NFB activation.

Methods and Results— To investigate the role of SMS2 in NFB activation we used macrophages from SMS2 knockout (KO) mice and SMS2 siRNA-treated HEK 293 cells. We found that NFB 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)– simulation. In line with attenuated NFB 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--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 NFB activation.

Conclusions— SMS2 is a modulator of NFB activation, and thus it could play an important role in NFB-mediated proatherogenic process.

Key Words: sphingomyelin synthase 2 • sphingomyelin • lipid rafts • NFB • atherosclerosis

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