title: The iNOS/Src/FAK axis contributes to lithium chloride-mediated macrophage migration.
abstract: Lithium chloride (LiCl) has long been used as a mood stabilizer for bipolar mood depression patients. However, its biological effects on immune cells are unclear yet. In this study, we observed that upon LiCl stimulation, the motility and the content of total protein tyrosine phosphorylation in RAW264.7 macrophages and murine peritoneal macrophages (PEMs) were significantly increased. The inhibition of LiCl-induced macrophage migration by PP2 (an inhibitor for Src family kinases (SFKs)) suggested the involvement of SFKs in this process. Interestingly, LiCl induced NF-kB activation, and while Src was greatly induced, the expression of its myeloid relatives (i.e. Lyn, Fgr, Hck) was almost unaltered in RAW264.7 cells. Knockdown of Src suppressed LiCl-elicited movement and the level of FAK Pi-Tyr861, which could be reversed by siRNA-resistant Src. Consistent with Src and migration increment was iNOS-dependent in macrophages, markedly reduced Src expression, activity and cell migration were observed in iNOS-null PEMs treated with LiCl. Moreover, FAK knockdown suppressed LiCl-stimulated macrophage motility, suggesting the involvement of FAK in this process. Remarkably, similar increment of iNOS, Src, FAK Pi-Tyr861 and migration ability could also be detected in RAW264.7 treated with other GSK3β inhibitors (i.e. SB216763 and Kenpaullone). These results corroborate that through inhibition of GSK3β, the iNOS/Src/FAK axis occupies a critical role in macrophage locomotion in response to LiCl.
authors: Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan; Ph.D. Program for Aging, China Medical University, Taichung 40402, Taiwan.
authors: Hui-Chen
authors: HC
authors: Chen
authors: Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.
authors: Wan-Chu
authors: WC
authors: Chien
authors: Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan.
authors: Miao Ying
authors: MY
authors: Chang
authors: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan; Department of Pharmacology, National Cheng Kung University, Tainan 70101, Taiwan.
authors: Ming-Yu
authors: MY
authors: Hsieh
authors: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors: Ming-Der
authors: MD
authors: Lai
authors: Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan; Ph.D. Program for Aging, China Medical University, Taichung 40402, Taiwan. Electronic address: mcmaa@mail.cmu.edu.tw.
authors: Ming-Chei
authors: MC
authors: Maa
authors: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan; Department of Pharmacology, National Cheng Kung University, Tainan 70101, Taiwan. Electronic address: tzengleu@mail.ncku.edu.tw.
authors: Tzeng-Horng
authors: TH
authors: Leu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D018021:Lithium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C412373:AG 1879; D011743:Pyrimidines; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051417:Focal Adhesion Kinase 1; D019061:src-Family Kinases; D018021:Lithium Chloride
keywords: FAK; GSK3β; LiCl; Macrophage migration; Src; iNOS