Requirement of inducible nitric-oxide synthase in lipopolysaccharide- mediated Src induction and macrophage migration

Ming Chei Maa, Ying Chang Miao, Yen Jen Chen, Chen Hsuan Lin, Jen Yu Chih, Lun Yang Yi, Jiarung Li, Pei Ru Chen, Chih Hsin Tang, Huan Yao Lei, Tzeng-Horng Leu

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Abstract

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 NOdonor) or 8-Br-cGMP (acGMPanalogue) 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.

Original languageEnglish
Pages (from-to)31408-31416
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number46
DOIs
Publication statusPublished - 2008 Nov 14

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Maa, M. C., Miao, Y. C., Chen, Y. J., Lin, C. H., Chih, J. Y., Yi, L. Y., Li, J., Chen, P. R., Tang, C. H., Lei, H. Y., & Leu, T-H. (2008). Requirement of inducible nitric-oxide synthase in lipopolysaccharide- mediated Src induction and macrophage migration. Journal of Biological Chemistry, 283(46), 31408-31416. https://doi.org/10.1074/jbc.M801158200