Mechanism of TNFα-induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts

Effects of statins and thiazolidinediones

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

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)81-90
Number of pages10
JournalCardiovascular Research
Volume76
Issue number1
DOIs
Publication statusPublished - 1 Oct 2007
Externally publishedYes

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Thiazolidinediones
Interleukin-1
Interleukin-6
Tumor Necrosis Factor-alpha
Fibroblasts
Cytokines
MAP Kinase Kinase 3
1-Phosphatidylinositol 4-Kinase
rosiglitazone
fluvastatin
troglitazone
p38 Mitogen-Activated Protein Kinases
Messenger RNA
Anti-Inflammatory Agents
Phospho-Specific Antibodies
Atrial Appendage
Simvastatin
Neutralizing Antibodies
Immunoblotting

Cite this

Turner, Neil A. ; Mughal, Romana S. ; Warburton, Philip ; O'Regan, David J. ; Ball, Stephen G. ; Porter, Karen E. / Mechanism of TNFα-induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts : Effects of statins and thiazolidinediones. In: Cardiovascular Research. 2007 ; Vol. 76, No. 1. pp. 81-90.
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abstract = "Objective: In addition to direct effects on myocardial cell function, tumor necrosis factor α (TNFα) 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 TNFα 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: TNFα (0.1-10 ng/ml) stimulated IL-6, IL-1α and IL-1β mRNA expression in cardiac fibroblasts in a concentration-dependent manner. Pharmacological inhibitors and receptor-neutralizing antibodies established that both TNFα-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)-κB pathways. In contrast, TNFα-induced IL-1α expression required both TNFRI and TNFRII subtypes and p38 MAPK and PI3K/Akt pathways, but was negatively regulated by the NF-κB pathway. Neither statins (simvastatin, fluvastatin) nor TZDs (ciglitazone, rosiglitazone, troglitazone) had inhibitory effects on TNFα-induced IL-6 secretion or IL-1α/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 TNFα-induced IL-1 or IL-6 expression by cardiac fibroblasts.",
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Mechanism of TNFα-induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts : Effects of statins and thiazolidinediones. / Turner, Neil A.; Mughal, Romana S.; Warburton, Philip; O'Regan, David J.; Ball, Stephen G.; Porter, Karen E.

In: Cardiovascular Research, Vol. 76, No. 1, 01.10.2007, p. 81-90.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mechanism of TNFα-induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts

T2 - Effects of statins and thiazolidinediones

AU - Turner, Neil A.

AU - Mughal, Romana S.

AU - Warburton, Philip

AU - O'Regan, David J.

AU - Ball, Stephen G.

AU - Porter, Karen E.

PY - 2007/10/1

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N2 - Objective: In addition to direct effects on myocardial cell function, tumor necrosis factor α (TNFα) 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 TNFα 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: TNFα (0.1-10 ng/ml) stimulated IL-6, IL-1α and IL-1β mRNA expression in cardiac fibroblasts in a concentration-dependent manner. Pharmacological inhibitors and receptor-neutralizing antibodies established that both TNFα-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)-κB pathways. In contrast, TNFα-induced IL-1α expression required both TNFRI and TNFRII subtypes and p38 MAPK and PI3K/Akt pathways, but was negatively regulated by the NF-κB pathway. Neither statins (simvastatin, fluvastatin) nor TZDs (ciglitazone, rosiglitazone, troglitazone) had inhibitory effects on TNFα-induced IL-6 secretion or IL-1α/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 TNFα-induced IL-1 or IL-6 expression by cardiac fibroblasts.

AB - Objective: In addition to direct effects on myocardial cell function, tumor necrosis factor α (TNFα) 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 TNFα 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: TNFα (0.1-10 ng/ml) stimulated IL-6, IL-1α and IL-1β mRNA expression in cardiac fibroblasts in a concentration-dependent manner. Pharmacological inhibitors and receptor-neutralizing antibodies established that both TNFα-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)-κB pathways. In contrast, TNFα-induced IL-1α expression required both TNFRI and TNFRII subtypes and p38 MAPK and PI3K/Akt pathways, but was negatively regulated by the NF-κB pathway. Neither statins (simvastatin, fluvastatin) nor TZDs (ciglitazone, rosiglitazone, troglitazone) had inhibitory effects on TNFα-induced IL-6 secretion or IL-1α/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 TNFα-induced IL-1 or IL-6 expression by cardiac fibroblasts.

KW - Cytokines

KW - Interleukins

KW - Receptors

KW - Signal transduction

KW - Statins

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