This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Katsuyama, K. Articles by Hirata, Y. Search for Related Content PubMed PubMed Citation Articles by Katsuyama, K. Articles by Hirata, Y.

Role of Nuclear Factor-B Activation in Cytokine- and Sphingomyelinase-Stimulated Inducible Nitric Oxide Synthase Gene Expression in Vascular Smooth Muscle Cells¹

Endocrine-Hypertension Division, Second Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo 113, Japan

Address all correspondence and requests for reprints to: Yukio Hirata, M.D., Endocrine-Hypertension Division, Second Department of Internal Medicine, Tokyo Medical and Dental University, 1–5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

Inflammatory cytokines, such as interleukin-1ß (IL-1ß) and tumor necrosis factor- (TNF), are known to activate sphingomyelinase (SMase) and nuclear factor-B (NF-B) in certain cell types, which also stimulate inducible nitric oxide synthase (iNOS) gene in vascular smooth muscle cells (VSMCs). However, it remains unknown whether the SMase pathway is involved in iNOS gene expression in VSMCs. Therefore, the present study was designed to examine whether SMase induces iNOS gene expression via the NF-B activation pathway similar to that of IL-1ß and TNF in cultured rat VSMCs. Neutral SMase, although less potently than IL-1ß and TNF, stimulated nitrite/nitrate (NOx) production, and iNOS messenger RNA and protein expression, as assessed by Northern and Western blot analyses, respectively. Neutral SMase, IL-1ß, and TNF activated NF-B, as revealed by electrophoretic mobility shift assay, and its nuclear translocation, as demonstrated by immunocytochemical study. Neutral SMase potentiated NOx production, iNOS expression, and NF-B activation stimulated by TNF, but not by IL-1ß. Aldehyde peptide proteasome inhibitors completely blocked NOx production, iNOS expression, NF-B activation, and its nuclear translocation induced by cytokines and neutral SMase. IL-1ß and TNF, but not neutral SMase, caused a transient decrease in IB- protein levels, whereas IB-ß protein expression was not affected by either agent. Proteasome inhibitors prevented cytokine-mediated IB- degradation. Several cell-permeable ceramide analogs (C2, C6, and C8), hydrolysis products of sphingomyelin, activated NF-B less potently than neutral SMase, but had no effect on NOx production. These results demonstrate an essential role of NF-B activation in mediation of neutral SMase-induced iNOS expression, but distinct from the proteasome-mediated IB- degradation by cytokines, suggesting the possible involvement of an additional signaling pathway(s).

This article has been cited by other articles:

				C. Shao, M. Folkard, B. D. Michael, and K. M. Prise Targeted cytoplasmic irradiation induces bystander responses PNAS, September 14, 2004; 101(37): 13495 - 13500. [Abstract] [Full Text] [PDF]

				M. Czarny, J. Liu, P. Oh, and J. E. Schnitzer Transient Mechanoactivation of Neutral Sphingomyelinase in Caveolae to Generate Ceramide J. Biol. Chem., February 7, 2003; 278(7): 4424 - 4430. [Abstract] [Full Text] [PDF]

				R. P. Cherla and R. K. Ganju Stromal Cell-Derived Factor 1{{alpha}}-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways J. Immunol., March 1, 2001; 166(5): 3067 - 3074. [Abstract] [Full Text] [PDF]

				R. H. UNGER and L. ORCI Diseases of liporegulation: new perspective on obesity and related disorders FASEB J, February 1, 2001; 15(2): 312 - 321. [Abstract] [Full Text] [PDF]

				M. Satoh, I. Date, M. Nakajima, K. Takahashi, K. Iseda, T. Tamiya, T. Ohmoto, Y. Ninomiya, S. Asari, and R. L. Macdonald Inhibition of Poly(ADP-Ribose) Polymerase Attenuates Cerebral Vasospasm After Subarachnoid Hemorrhage in Rabbits Editorial Comment Stroke, January 1, 2001; 32(1): 225 - 231. [Abstract] [Full Text] [PDF]

				L. R. Vann, S. Twitty, S. Spiegel, and S. Milstien Divergence in Regulation of Nitric-oxide Synthase and Its Cofactor Tetrahydrobiopterin by Tumor Necrosis Factor-alpha . CERAMIDE POTENTIATES NITRIC OXIDE SYNTHESIS WITHOUT AFFECTING GTP CYCLOHYDROLASE I ACTIVITY J. Biol. Chem., April 28, 2000; 275(18): 13275 - 13281. [Abstract] [Full Text] [PDF]

				T. Kislinger, C. Fu, B. Huber, W. Qu, A. Taguchi, S. Du Yan, M. Hofmann, S. F. Yan, M. Pischetsrieder, D. Stern, et al. Nepsilon -(Carboxymethyl)Lysine Adducts of Proteins Are Ligands for Receptor for Advanced Glycation End Products That Activate Cell Signaling Pathways and Modulate Gene Expression J. Biol. Chem., October 29, 1999; 274(44): 31740 - 31749. [Abstract] [Full Text] [PDF]

				K. Katsuyama, M. Shichiri, H. Kato, T. Imai, F. Marumo, and Y. Hirata Differential Inhibitory Actions by Glucocorticoid and Aspirin on Cytokine-Induced Nitric Oxide Production in Vascular Smooth Muscle Cells Endocrinology, May 1, 1999; 140(5): 2183 - 2190. [Abstract] [Full Text]