Gene interactions and pathways from curated databases and text-mining
Cardiovasc Res 2007, PMID: 17612514

Mechanism of TNFalpha-induced IL-1alpha, IL-1beta 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

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.

Diseases/Pathways annotated by Medline MESH: Coronary Disease
Document information provided by NCBI PubMed

Text Mining Data

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

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

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

IL-1alpha → TNFalpha: " TNFalpha ( 0.1-10 ng/ml ) stimulated IL-6, IL-1alpha and IL-1beta mRNA expression in cardiac fibroblasts in a concentration dependent manner "

IL-1beta → TNFalpha: " TNFalpha ( 0.1-10 ng/ml ) stimulated IL-6, IL-1alpha and IL-1beta mRNA expression in cardiac fibroblasts in a concentration dependent manner "

IL-6 → TNFalpha: " TNFalpha ( 0.1-10 ng/ml ) stimulated IL-6 , IL-1alpha and IL-1beta mRNA expression in cardiac fibroblasts in a concentration dependent manner "

IL-1beta → TNFalpha: " 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 "

IL-6 → TNFalpha: " 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 "

IL-1alpha → TNFalpha: " 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 "

IL-1alpha/beta → TNFalpha: " 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 "

IL-6 → TNFalpha: " 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 "

IL-1 → TNFalpha: " 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 "

Manually curated Databases

No curated data.