Copyright © 2007, European Society of Cardiology
Mechanism of TNF
-induced IL-1, IL-1β and IL-6 expression in human cardiac fibroblasts: Effects of statins and thiazolidinediones
aAcademic Unit of Cardiovascular Medicine, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds LS2 9JT, UK
bDepartment of Cardiac Surgery, The Yorkshire Heart Centre, Leeds General Infirmary, Leeds LS1 3EX, UK
*Corresponding author. Tel.: +44 113 3435890; fax: +44 113 3434803. n.a.turner{at}leeds.ac.uk
Objective In addition to direct effects on myocardial cell function, tumor necrosis factor 
(TNF) contributes to adverse cardiac remodeling by increasing production of other pro-inflammatory cytokines [e.g. interleukin (IL)-1 and IL-6]. Both statins and thiazolidinediones (TZDs) have beneficial effects on cardiac remodeling, possibly due to their anti-inflammatory properties. The present study examined the mechanisms by which TNF stimulates expression of pro-inflammatory cytokines in cultured human cardiac fibroblasts and determined the effects of statin or TZD treatment.
Methods Human cardiac fibroblasts were cultured from biopsies of right atrial appendages. Cytokine mRNA expression and secretion was measured using quantitative real-time RT-PCR and ELISA. Activation of signaling pathways was determined by immunoblotting with phospho-specific antibodies.
Results TNF (0.1–10 ng/ml) stimulated IL-6, IL-1 and IL-1β mRNA expression in cardiac fibroblasts in a concentration-dependent manner. Pharmacological inhibitors and receptor-neutralizing antibodies established that both TNF-induced IL-6 and IL-1β expression was mediated via the TNFRI receptor and p38 mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt and nuclear factor (NF)-
B pathways. In contrast, TNF-induced IL-1 expression required both TNFRI and TNFRII subtypes and p38 MAPK and PI3K/Akt pathways, but was negatively regulated by the NF-B pathway. Neither statins (simvastatin, fluvastatin) nor TZDs (ciglitazone, rosiglitazone, troglitazone) had inhibitory effects on TNF-induced IL-6 secretion or IL-1/β mRNA expression; indeed, cytokine expression was increased in response to TZDs.
Conclusions Our data provide important insights into the regulation of pro-inflammatory cytokine expression in human cardiac fibroblasts and suggest that the myocardial anti-inflammatory effects of statins and TZDs are not due to inhibition of TNF-induced IL-1 or IL-6 expression by cardiac fibroblasts.
KEYWORDS Cytokines; Interleukins; Receptors; Signal transduction; Statins
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. A. Madi, K. Riches, P. Warburton, D. J. O'Regan, N. A. Turner, and K. E. Porter Inherent differences in morphology, proliferation, and migration in saphenous vein smooth muscle cells cultured from nondiabetic and Type 2 diabetic patients Am J Physiol Cell Physiol, November 1, 2009; 297(5): C1307 - C1317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. A. Turner, A. Das, P. Warburton, D. J. O'Regan, S. G. Ball, and K. E. Porter Interleukin-1{alpha} stimulates proinflammatory cytokine expression in human cardiac myofibroblasts Am J Physiol Heart Circ Physiol, September 1, 2009; 297(3): H1117 - H1127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Palomer, D. Alvarez-Guardia, R. Rodriguez-Calvo, T. Coll, J. C. Laguna, M. M. Davidson, T. O. Chan, A. M. Feldman, and M. Vazquez-Carrera TNF-{alpha} reduces PGC-1{alpha} expression through NF-{kappa}B and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model Cardiovasc Res, March 1, 2009; 81(4): 703 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. I. Totlandsdal, M. Refsnes, T. Skomedal, J.-B. Osnes, P. E. Schwarze, and M. Lag Particle-Induced Cytokine Responses in Cardiac Cell Cultures--the Effect of Particles versus Soluble Mediators Released by Particle-Exposed Lung Cells Toxicol. Sci., November 1, 2008; 106(1): 233 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Park, S. Capobianco, X. Gao, J. R. Falck, K. C. Dellsperger, and C. Zhang Role of EDHF in type 2 diabetes-induced endothelial dysfunction Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H1982 - H1988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Guy, D. W. Lambert, A. J. Turner, and K. E. Porter Functional angiotensin-converting enzyme 2 is expressed in human cardiac myofibroblasts Exp Physiol, May 1, 2008; 93(5): 579 - 588. [Abstract] [Full Text] [PDF]
|
|