This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/12/2622    most recent 01.ATV.0000246779.78003.cfv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, F.-Y. Articles by Lin, S.-J. Search for Related Content PubMed PubMed Citation Articles by Lin, F.-Y. Articles by Lin, S.-J. Related Collections Animal models of human disease Cell biology/structural biology Mechanism of atherosclerosis/growth factors Other Vascular biology Related Article

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2622.)
© 2006 American Heart Association, Inc.

Vascular Biology

The Role of Human Antigen R, an RNA-binding Protein, in Mediating the Stabilization of Toll-Like Receptor 4 mRNA Induced by Endotoxin

A Novel Mechanism Involved in Vascular Inflammation

Feng-Yen Lin; Yung-Hsiang Chen; Yi-Wen Lin; Jen-Sung Tsai; Jaw-Wen Chen; Hsiao-Jung Wang; Yuh-Lien Chen; Chi-Yuan Li; Shing-Jong Lin

From the Graduate Institute of Medical Sciences (F.Y.L.), Graduate Institute of Life Sciences (Y.W.L.), Departments of Anesthesiology (C.Y.L.), Departments of Cardiovascular Surgery (J.S.T.), Tri-service General Hospital, National Defense Medical Center; Institute of Clinical Medicine (Y.H.C., H.J.W., S.J.L.), and Cardiovascular Research Center (J.W.C., S.J.L.), National Yang-Ming University; Division of Cardiology (J.W.C., S.J.L.), Taipei Veterans General Hospital; Department of Medical Education and Research (C.Y.L.), Buddhist Tzu-Chi General Hospital; Department of Anatomy and Cell Biology (Y.L.C.), College of Medicine, National Taiwan University, Taipei, Taiwan.

Correspondence to Dr Shing-Jong Lin, Division of Cardiology, Taipei Veterans General Hospital, 201, Sec. 2, Shi-Pai Rd., Taipei 112, Tawian. E-mail sjlin{at}vghtpe.gov.tw; Dr Yuh-Lien Chen, ylchen@ha.mc.ntu.edu.tw; Dr Chi-Yuan Li, cyli@ndmctsgh.edu.tw

Objective— Lipopolysaccharide (LPS) interacts with toll-like receptor 4 (TLR4) and induces proliferation of vascular smooth muscle cells (VSMCs) which plays a causal role in atherogenesis. The role of TLR4 expression and regulation in LPS-stimulated VSMCs remains unclear. TLR4 mRNAs often contain AU-rich elements (AREs) in their 3' untranslated regions (3'UTR) which have a high affinity for RNA-binding proteins. It is not know whether the RNA-binding protein, human antigen R (HuR), regulates TLR4 expression in human aortic smooth muscle cells (HASMCs).

Methods and Results— Stimulation of HASMCs with LPS significantly increased the cytosolic HuR level in vitro. Immunoprecipitation and RT-PCR demonstrated that LPS markedly increased the interaction of HuR and 3'UTR of TLR4 mRNA. The reporter plasmid, which contains the 3'UTR of TLR4 mRNA, significantly increased luciferase reporter gene expression in LPS-induced HASMCs. These data suggest that the 3'UTR of TLR4 mRNA confers LPS responsiveness and that HuR modulates 3'UTR-mediated gene expression. Knock-down of HuR inhibited LPS-induced TLR4 mRNA stability in HASMCs and luciferase reporter gene expression in CMV-Luciferase-TLR4 3'UTR-transfected HASMCs. In addition, inhibition of NADPH oxidase activity by diphenylene iodonium, knock-down of Rac1 gene expression by siRNA, and decrease of p38 MAPK activity by SB203580 significantly decreased the cytosolic HuR level, which mediates TLR4 mRNA stability.

Conclusion— Activation of NADPH oxidase and the MAPK-signaling pathway contribute to HuR-mediated stabilization of TLR4 mRNA induced by LPS in HASMCs. In the balloon injured rabbit aorta model, systemic inflammation induced by LPS caused intimal hyperplasia and increased TLR4 and HuR expression.

We investigated the posttranscriptional regulation in LPS-induced TLR4 expression in HASMCs and balloon-injured rabbit aorta. These results demonstrate that activation of NADPH oxidase and the MAPK-signaling pathway contribute to HuR-mediated stabilization of TLR4 mRNA induced by LPS in smooth muscle cells.

Key Words: LPS • toll-like receptor • human antigen R • inflammation • vascular smooth muscle cell (VSMC)

Related Article:

Regulation of TLR4 Expression Is a Tale About Tail

Zhong-qun Yan
Arterioscler Thromb Vasc Biol 2006 26: 2582-2584. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				C. Tiruppathi, J. Shimizu, K. Miyawaki-Shimizu, S. M. Vogel, A. M. Bair, R. D. Minshall, D. Predescu, and A. B. Malik Role of NF-{kappa}B-dependent Caveolin-1 Expression in the Mechanism of Increased Endothelial Permeability Induced by Lipopolysaccharide J. Biol. Chem., February 15, 2008; 283(7): 4210 - 4218. [Abstract] [Full Text] [PDF]

				E. J. Quann, F. Khwaja, and D. Djakiew The p38 MAPK Pathway Mediates Aryl Propionic Acid Induced Messenger RNA Stability of p75NTR in Prostate Cancer Cells Cancer Res., December 1, 2007; 67(23): 11402 - 11410. [Abstract] [Full Text] [PDF]

				K. S. A. Khabar Rapid transit in the immune cells: the role of mRNA turnover regulation J. Leukoc. Biol., June 1, 2007; 81(6): 1335 - 1344. [Abstract] [Full Text] [PDF]

				Z.-q. Yan Regulation of TLR4 Expression Is a Tale About Tail. Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2582 - 2584. [Full Text] [PDF]