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J. Biol. Chem., Vol. 283, Issue 46, 31408-31416, November 14, 2008

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Requirement of Inducible Nitric-oxide Synthase in Lipopolysaccharide-mediated Src Induction and Macrophage Migration^*

Ming-Chei Maa¹, Miao Ying Chang, Yen-Jen Chen, Chen-Hsuan Lin^¶, Chih Jen Yu^¶, Yi Lun Yang^¶, Jiarung Li^¶, Pei-Ru Chen^||, Chih-Hsin Tang^**, Huan-Yao Lei, and Tzeng-Horng Leu²

From the Institute of Medical Science, China Medical University, Taichung 40402, the Institute of Basic Medical Sciences, Department of Pharmacology, College of Medicine, and the Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 70101, the ^¶Institute of Biochemistry and Biotechnology, ^||Instrument Center, Chung Shan Medical University, Taichung 40201 the ^**Department of Pharmacology, China Medical University, Taichung 40402, and the Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan

Previously, we have demonstrated the induction of Src in lipopolysaccharide (LPS)-stimulated macrophages. In this study, we observed that pharmacological blockade or knockout of inducible nitric-oxide synthase (iNOS) reduced LPS-mediated Src induction and macrophage migration. Either SNAP (a NO donor) or 8-Br-cGMP (a cGMP analogue) could rescue these defects in iNOS-null macrophages, which indicated the participation of NO/cGMP in LPS-elicited Src expression and mobilization. In addition, Src family kinase (SFK)-specific inhibitor, PP2, inhibited SNAP- and 8-Br-cGMP-evoked motility implicating the involvement of SFKs downstream of NO/cGMP. Analysis of the expression of SFKs indicated LPS dramatically induced Src, which could be attributable to the increased level of the src transcript. Attenuation of Src by src-specific siRNA reduced LPS- and SNAP-evoked mobilization in Raw264.7 macrophages, and reintroduction of avian Src could rescue their motility. Furthermore, LPS-mediated Src induction led to increased FAK Pi-Tyr-397 and Pi-Tyr-861, which was also iNOS-dependent. With these findings, we concluded that iNOS was important for LPS-mediated macrophage locomotion and Src was a critical player in this process.

Received for publication, February 12, 2008 , and in revised form, August 28, 2008.

^* This work was supported by the National Science Council (NSC) (Grant NSC95-2311-B-039-001-MY3 to M.-C. M. and Grant NSC95-2320-B-006-074-MY2 to T.-H. L.). Additional support came from National Health Research Institute (Grant NHRI-EX-97-9517BI) and China Medical University Grants CMU95-306 and CMU96-134 (to T.-H. L. and M.-C. M., respectively). The DNA construct pLKO.1-msrc (puro) was provided by the National RNAi Core Facility located at the institute of Molecular Biology/Genomic Research Center, Academia Sinica, supported by the National Research Program for Genomic Medicine Grants of NSC (Grants NSC 94-3112-B-001-003 and NSC 94-3112-B-001-018-Y). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence may be addressed. Tel.: 886-4-2205-2121 (ext. 7708); Fax: 886-4-2205-3764; E-mail: mcmaa{at}mail.cmu.edu.tw. ² To whom correspondence may be addressed. Tel.: 886-6-235-3535 (ext. 5468); Fax: 886-6-274-9296; E-mail: tzengleu{at}mail.ncku.edu.tw.

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