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Br J Pharmacol. 2010 Apr;159(8):1598-607. doi: 10.1111/j.1476-5381.2009.00558.x. Epub 2009 Dec 24.

Stimulation of adenosine A(2B) receptors induces interleukin-6 secretion in cardiac fibroblasts via the PKC-delta-P38 signalling pathway.

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  • 1Institute of Vascular Medicine, Peking University Third Hospital, Ministry of Education, Beijing, China.

Abstract

BACKGROUND AND PURPOSE:

Inflammatory response and cytokine activation are markedly stimulated after myocardial infarction, and contribute to cardiac remodelling. Interleukin-6 (IL-6), a pro-inflammatory cytokine, has pleiotropic effects on cardiac remodelling. Adenosine, released by all cell types, binds to a class of G protein-coupled receptors to induce various cardiovascular effects. The aim of this work was to investigate whether activation of adenosine receptors, particularly A(2B) adenosine receptors, could stimulate IL-6 secretion in cardiac fibroblasts (CFs).

EXPERIMENTAL APPROACH:

elisa was used to assess IL-6 concentration in supernatant, and immunostaining was used to analyse IL-6 protein level in CFs. The levels of phosphorylated and total p38, extracellular signal-regulated kinase, c-Jun N-terminal kinase and protein kinase C-delta (PKC-delta) were determined by Western blot analysis.

KEY RESULTS:

Adenosine-5'-N-ethyluronamide (NECA), a stable adenosine analogue, dose- and time-dependently stimulated IL-6 secretion in CFs. The effect of NECA was dose-dependently inhibited by an A(2B) antagonist, and silencing of the A(2B) receptor also inhibited IL-6 secretion. By using PKC isoform-selective inhibitors and translocation peptide inhibitors, the PKC-delta isoform was found to be involved in the up-regulation of IL-6 production. Inhibition of p38 by SB203580, and adenoviral transfer of dominant-negative p38 inhibited NECA-induced IL-6 production. Furthermore, PKC-delta functioned as an upstream regulator of p38 MAPK in this process.

CONCLUSIONS AND IMPLICATIONS:

We demonstrated a novel relationship between adenosine and IL-6 secretion, in that IL-6 secretion induced by NECA was mediated by adenosine A(2B) receptor activation in CFs and was dependent on a PKCdelta-P38 pathway.

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PMID:
20050850
[PubMed - indexed for MEDLINE]
PMCID:
PMC2925484
Free PMC Article
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