HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/H1117    most recent 00372.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Turner, N. A. Articles by Porter, K. E. PubMed PubMed Citation Articles by Turner, N. A. Articles by Porter, K. E.

Interleukin-1 stimulates proinflammatory cytokine expression in human cardiac myofibroblasts

¹Division of Cardiovascular and Neuronal Remodelling, Leeds Institute of Genetics, Health, and Therapeutics and ²Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds; and ³Department of Cardiac Surgery, The Yorkshire Heart Centre, Leeds General Infirmary, Leeds, United Kingdom

Submitted 14 April 2009 ; accepted in final form 21 July 2009

Cardiac myofibroblasts (CMF) play a key role in infarct repair and scar formation following myocardial infarction (MI) and are also an important source of proinflammatory cytokines. We postulated that interleukin-1 (IL-1), a potential early trigger of acute inflammation post-MI, could stimulate human CMF to express additional proinflammatory cytokines. Furthermore, we hypothesized that these effects may be modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). Human CMF were cultured from atrial biopsies from multiple patients. Interleukin-1β (IL-1β), tumor necrosis factor- (TNF-), interleukin-6 (IL-6), and cardiotrophin-1 (CT-1) mRNA expression and secretion were measured using quantitative real-time RT-PCR and enzyme-linked immunosorbent assay. IL-1 (0.001–10 ng/ml, 0–6 h) stimulated IL-1β, TNF-, and IL-6 mRNA expression with distinct temporal and concentration profiles, resulting in increased cytokine secretion. The response to IL-1 was much greater than with TNF-. Neither IL-1 nor TNF- treatment modulated CT-1 mRNA expression. Immunoblotting with phosphospecific antibodies revealed that IL-1 stimulated the extracellular signal-regulated kinase (ERK)-1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun NH₂-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), and nuclear factor (NF)-B signaling pathways. Pharmacological inhibitor studies indicated roles for PI 3-kinase/Akt and NF-B pathways in mediating IL-1β expression, and for NF-B and p38 MAPK pathways in mediating TNF- expression. IL-1-induced IL-6 mRNA expression was reduced by p38 MAPK inhibition, but increased by ERK and JNK pathway inhibitors. IL-10 produced a consistent but modest reduction in IL-1-induced IL-6 mRNA levels (not IL-1β or TNF-), but this was not reflected by reduced IL-6 protein secretion. In conclusion, IL-1 stimulates human CMF to express IL-1β, TNF-, and IL-6 via specific signaling pathways, responses that are unaffected by IL-10 exposure.

cardiac fibroblasts; inflammation; signal transduction; cytokines; interleukin-10