Mechanism of TNFalpha-induced IL-1alpha, IL-1beta and IL-6 expression in human cardiac fibroblasts: effects of statins and thiazolidinediones.

Mechanism of TNFalpha-induced IL-1alpha, IL-1beta and IL-6 expression in human cardiac fibroblasts: effects of statins and thiazolidinediones. Research Abstract Details 

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Mechanism of TNFalpha-induced IL-1alpha, IL-1beta and IL-6 expression in human cardiac fibroblasts: effects of statins and thiazolidinediones. Abstract Text:

Neil A Turner,Romana S Mughal,Philip Warburton,David J O'Regan,Stephen G Ball,Karen E Porter,

OBJECTIVE: In addition to direct effects on myocardial cell function, tumor necrosis factor alpha (TNFalpha) 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 TNFalpha 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: TNFalpha (0.1-10 ng/ml) stimulated IL-6, IL-1alpha and IL-1beta mRNA expression in cardiac fibroblasts in a concentration-dependent manner. Pharmacological inhibitors and receptor-neutralizing antibodies established that both TNFalpha-induced IL-6 and IL-1beta expression was mediated via the TNFRI receptor and p38 mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt and nuclear factor (NF)-kappaB pathways. In contrast, TNFalpha-induced IL-1alpha expression required both TNFRI and TNFRII subtypes and p38 MAPK and PI3K/Akt pathways, but was negatively regulated by the NF-kappaB pathway. Neither statins (simvastatin, fluvastatin) nor TZDs (ciglitazone, rosiglitazone, troglitazone) had inhibitory effects on TNFalpha-induced IL-6 secretion or IL-1alpha/beta 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 TNFalpha-induced IL-1 or IL-6 expression by cardiac fibroblasts.

Mechanism of TNFalpha-induced IL-1alpha, IL-1beta and IL-6 expression in human cardiac fibroblasts: effects of statins and thiazolidinediones. Publishing Authors By Initials

NA Turner,RS Mughal,P Warburton,DJ O'Regan,SG Ball,KE Porter,

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Mechanism of TNFalpha-induced IL-1alpha, IL-1beta and IL-6 expression in human cardiac fibroblasts: effects of statins and thiazolidinediones. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cardiovascular research

VOLUME: 76

Page Numbers: 81-90

Journal Abbreviation: Cardiovasc. Res.

ISSN: 0008-6363

DAY: 12

MONTH: 06

YEAR: 2007

Mechanism of TNFalpha-induced IL-1alpha, IL-1beta and IL-6 expression in human cardiac fibroblasts: effects of statins and thiazolidinediones. Information

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LANGUAGE: eng

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AFFILIATION: Academic Unit of Cardiovascular Medicine, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds LS2 9JT, UK. n.a.turner@leeds.ac.uk

Country: Netherlands

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MEDLINETA: Cardiovasc Res

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