title: A physiological concentration of glucocorticoid inhibits the pro-inflammatory cytokine-induced proliferation of adult rat cardiac fibroblasts: roles of extracellular signal-regulated kinase 1/2 and nuclear factor-κB.
abstract: 1. Inflammation-induced proliferation of cardiac fibroblasts plays an important role in cardiac remodelling. Pharmacological doses of exogenous glucocorticoids (GC) are the most effective therapy for inflammatory diseases. Similarly, physiological concentrations of endogenous GC have recently been shown to have anti-inflammatory effects. Therefore, the aim of the present study was to determine whether a physiological concentration of GC could inhibit pro-inflammatory cytokine-stimulated proliferation of cardiac fibroblasts and to explore the mechanisms involved. 2. Cardiac fibroblasts were isolated from adult male Sprague-Dawley rats and cell proliferation was measured using a CCK-8 kit. Western blotting was used to detect protein expression of extracellular-regulated kinase (ERK) 1/2 and nuclear factor (NF)-κB. 3. Cardiac fibroblast proliferation was significantly increased by tumour necrosis factor-α, interleukin (IL)-1β and angiotensin II and was accompanied by upregulated protein expression of ERK1/2 and NF-κB. A physiological concentration of hydrocortisone (127 ng/mL) not only inhibited the proliferation of cardiac fibroblasts, but also suppressed activation of ERK1/2 and NF-κB. These effects of hydrocortisone were abrogated by the glucocorticoid receptor (GR) antagonist RU-486 (100 nmol/L). Furthermore, inflammation-induced cardiac fibroblast proliferation was also blocked by the mitogen-activated protein kinase kinase 1/2 inhibitor U0126 (100 nmol/L) and the NF-κB inhibitor pyrrolidine dithiocarbamate (1 μmol/L). Cytokine-induced ERK1/2 phosphorylation and cyclin D1 expression were attenuated by U0126, suggesting that the ERK1/2 and NF-κB signalling pathways were involved in cardiac fibroblast proliferation. 4. In conclusion, the results of the present study indicate that a physiological concentration of hydrocortisone can inhibit inflammation-induced proliferation of cardiac fibroblasts by preventing the activation of ERK1/2 and NF-κB.
authors.affiliation: Department of Pharmacology, Guangzhou Key Laboratory of Cardiovascular Disease and the Second Affiliated Hospital, Guangzhou Medical University, China.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: He
authors.forename: Hai-Ning
authors.initials: HN
authors.lastname: Zhang
authors.forename: Gui-Ping
authors.initials: GP
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Hou
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiao
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.forename: Jian-Hui
authors.initials: JH
authors.lastname: Wu
authors.forename: Miao-Shan
authors.initials: MS
authors.lastname: Luo
authors.forename: Gen-Shui
authors.initials: GS
authors.lastname: Zhang
authors.forename: Quan
authors.initials: Q
authors.lastname: Yi
authors.forename: Min-Shen
authors.initials: MS
authors.lastname: Chen
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Luo
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D006854:Hydrocortisone / Q000494:pharmacology* / Q000502:physiology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: C530106:Ccnd1 protein, rat; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D019938:Cyclin D1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006854:Hydrocortisone