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.
| Language | English |
|---|---|
| Pages | 81-90 |
| Number of pages | 10 |
| Journal | Cardiovascular Research |
| Volume | 76 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Oct 2007 |
| Externally published | Yes |
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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 journal › Article
TY - JOUR
T1 - Mechanism of TNFα-induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts
T2 - Cardiovascular Research
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
Y1 - 2007/10/1
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
UR - http://www.scopus.com/inward/record.url?scp=34548452154&partnerID=8YFLogxK
U2 - 10.1016/j.cardiores.2007.06.003
DO - 10.1016/j.cardiores.2007.06.003
M3 - Article
VL - 76
SP - 81
EP - 90
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 1
ER -