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The Upregulation of Transglutaminase‐2 by Cyclosporin A in Human Gingival Fibroblasts Is Augmented by Oxidative Stress
Author(s) -
Lee ShiuanShinn,
Tsai ChungHung,
Kuan YuHsiang,
Huang FuMei,
Chang YuChao
Publication year - 2013
Publication title -
journal of periodontology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.036
H-Index - 156
eISSN - 1943-3670
pISSN - 0022-3492
DOI - 10.1902/jop.2012.120554
Subject(s) - curcumin , ly294002 , oxidative stress , reactive oxygen species , chemistry , p38 mitogen activated protein kinases , western blot , downregulation and upregulation , intracellular , pharmacology , mapk/erk pathway , kinase , protein kinase a , glutathione , cytotoxicity , extracellular , biochemistry , phosphatidylinositol , biology , enzyme , in vitro , gene
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.