title: Thrombomodulin regulates monocye differentiation via PKCδ and ERK1/2 pathway in vitro and in atherosclerotic artery.
abstract: Thrombomodulin (TM) modulates the activation of protein C and coagulation. Additionally, TM regulates monocyte migration and inflammation. However, its role on monocyte differentiation is still unknown. We investigated the effects of TM on monocyte differentiation. First, we found that TM was increased when THP-1 cells were treated with phorbol-12-myristate-13-acetate (PMA). Overexpression of TM enhanced the macrophage markers, CD14 and CD68 expression in PMA-induced THP-1. TM siRNA depressed the PMA-induced increase of p21Cip1/WAF1via ERK1/2-NF-kB p65 signaling. TM regulated cytoskeletal reorganization via its interaction with paxillin, cofilin, LIMK1, and PYK2. In addition, PMA-induced p21Cip1/WAF1expression, CD14-positive cell labeling intensity and ERK1/2 phosphorylation were markedly inhibited when protein kinase C-δ (PKCδ) was knocked down. We identified that TM directly interacts with PKCδ. PKCδ was highly expressed in human atherosclerotic arteries and colocalized with TM in CD68-positive infiltrated macrophages of plaques, indicating that the coordination between TM and PKCδ in macrophages participated in atherogenesis. TM may act as a scaffold for PKCδ docking, which keeps PKCδ in the region close to the monocyte membrane to promote the activation of ERK1/2. Taken together, our findings suggest that TM-PKCδ interaction may contribute to cardiovascular disorders by affecting monocye differentiation, which may develop future therapeutic applications.
authors.affiliation: Division of Cardiovascular Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.|Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.|Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan.|Division of Cardiovascular Surgery, Department of Surgery, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan.
authors.forename: Chien-Sung
authors.initials: CS
authors.lastname: Tsai
authors.affiliation: Division of Cardiovascular Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.|Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.|Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.|Departments of Internal Medicine, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun-Yao
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.|Departments of Internal Medicine, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun-Min
authors.initials: CM
authors.lastname: Shih
authors.affiliation: Division of Cardiovascular Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Tsai
authors.affiliation: Division of Cardiovascular Surgery, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Nai-Wen
authors.initials: NW
authors.lastname: Tsao
authors.affiliation: Division of Cardiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chin-Sheng
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chun-Che
authors.initials: CC
authors.lastname: Shih
authors.affiliation: Division of Anatomy and Cell Biology, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hellen
authors.initials: H
authors.lastname: Jeng
authors.affiliation: Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.|Departments of Internal Medicine, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Feng-Yen
authors.initials: FY
authors.lastname: Lin
mesh_terms: D001158:Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D051745:Protein Kinase C-delta / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage / Q000031:analogs & derivatives; D018180:Thrombomodulin / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; D018180:Thrombomodulin; C016658:phorbolol myristate acetate; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate