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Lipoteichoic Acid Induces HO-1 Expression via the TLR2/MyD88/c-Src/NADPH Oxidase Pathway and Nrf2 in Human Tracheal Smooth Muscle Cells¹

I-Ta Lee^*, Shyi-Wu Wang^*, Chiang-Wen Lee^*, Chia-Chi Chang^*, Chih-Chung Lin, Shue-Fen Luo and Chuen-Mao Yang^2,*

^* Department of Physiology and Pharmacology, Department of Anesthetics, and Department of Internal Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan

Heme oxygenase (HO)-1 is a stress-inducible rate-limiting enzyme in heme degradation that confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homeostasis. Increasing reports have indicated that lipoteichoic acid (LTA) exerts as LPS as an immune system-stimulating agent and plays a role in the pathogenesis of severe inflammatory responses induced by Gram-positive bacterial infection. We report that LTA is an inducer of HO-1 expression mediated through the signaling pathways in human tracheal smooth muscle cells (HTSMCs). LTA-induced HO-1 protein levels, mRNA expression, and promoter activity were attenuated by transfection with dominant negative mutants of TLR2 and MyD88, by pretreatment with the inhibitors of c-Src (PP1), NADPH oxidase (diphenylene iodonium chloride (DPI) and apocynin (APO)), and reactive oxygen species (ROS) scavenger (N-acetyl-L-cysteine) or by transfection with small interfering RNAs of Src and NF-E2-related factor 2 (Nrf2). LTA-stimulated translocation of p47^phox and Nrf2 or ROS production was attenuated by transfection with dominant negative mutants of TLR2, MyD88, and c-Src and by pretreatment with DPI or APO. Furthermore, LTA-induced TLR2, MyD88, TNFR-associated factor (TRAF)6, c-Src, and p47^phox complex formation was revealed by immunoprecipitation using an anti-TLR2 or anti-c-Src Ab followed by Western blot analysis against an anti-TLR2, anti-MyD88, anti-TRAF6, anti-c-Src, or anti-p47^phox Ab. These results demonstrated that LTA-induced ROS generation was mediated through the TLR2/MyD88/TRAF6/c-Src/NADPH oxidase pathway, in turn initiates the activation of Nrf2, and ultimately induces HO-1 expression in HTSMCs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants NSC95-2320-B182-010 (to C.M.Y.), NSC95-2314-B182-040 (to C.C.L.), NSC95-2314-B182-053 (to S.F.L.), CMRPD32043 (to C.M.Y.), and CMRPG350651 (to C.C.L.).

² Address correspondence and reprint requests to Dr. Chuen-Mao Yang, Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan. E-mail address: chuenmao{at}mail.cgu.edu.tw

³ Abbreviations used in this paper: ROS, reactive oxygen species; HO-1, heme oxygenase-1; LTA, lipoteichoic acid; siRNA, small interfering RNA; DPI, diphenylene iodonium chloride; APO, apocynin; ARE, antioxidant response element; TRAF, TNFR-associated factor; HTSMC, human tracheal smooth muscle cell; β-gal, β-galactosidase; Nrf, NF-E2-related factor; NAc, N-acetyl-L-cysteine.