title: The upregulation of transglutaminase-2 by cyclosporin a in human gingival fibroblasts is augmented by oxidative stress.
abstract: BACKGROUND
  Transglutaminase-2 (TGM-2) has been implicated in several fibrotic disorders and can be induced by reactive oxygen species (ROS). Hence, the authors hypothesize that cyclosporin A (CsA) may regulate TGM-2 via ROS, and this regulation may have a role in the pathogenesis of CsA-induced gingival overgrowth.
  
  
  METHODS
  Cytotoxicity, 2',7'-dichlorodihydrofluorescein diacetate assay, and Western blot were used to investigate the effects of CsA in human gingival fibroblasts (HGFs). In addition, extracellular signal-regulated kinase (ERK) inhibitor PD98059, phosphatidylinositol 3-kinase inhibitor LY294002, glutathione precursor N-acetyl-L-cysteine (NAC), curcumin, epigallocatechin-3 gallate (EGCG), and p38 inhibitor SB203580 were added to find the possible regulatory mechanisms.
  
  
  RESULTS
  Concentrations of CsA >500 ng/mL demonstrated cytotoxicity to HGFs (P < 0.05). CsA enhanced the generation of intracellular ROS at concentrations >200 ng/mL (P <0.05). TGM-2 protein induced by CsA was found in HGFs in a dose- and time-dependent manner (P <0.05). The addition of PD98059, LY294002, NAC, curcumin, EGCG, and SB203580 markedly inhibited TGM-2 expression induced by CsA (P <0.05).
  
  
  CONCLUSIONS
  These results demonstrate that CsA significantly upregulates intracellular ROS generation and elevates TGM-2 expression in HGFs. In addition, TGM-2 induced by CsA is downregulated by PD98059, LY294002, NAC, curcumin, EGCG, and SB203580.
authors.affiliation: School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shiuan-Shinn
authors.initials: SS
authors.lastname: Lee
authors.forename: Chung-Hung
authors.initials: CH
authors.lastname: Tsai
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Kuan
authors.forename: Fu-Mei
authors.initials: FM
authors.lastname: Huang
authors.forename: Yu-Chao
authors.initials: YC
authors.lastname: Chang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002867:Chromones; D003474:Curcumin / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D009025:Morpholines; D018384:Oxidative Stress / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016166:Free Radical Scavengers; D007093:Imidazoles; D007166:Immunosuppressive Agents; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011480:Protease Inhibitors; D011725:Pyridines; D017382:Reactive Oxygen Species; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016572:Cyclosporine; D002392:Catechin; C045651:epigallocatechin gallate; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D048049:Extracellular Signal-Regulated MAP Kinases; D019204:GTP-Binding Proteins; D003474:Curcumin; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000111:Acetylcysteine