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

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.

journal_name

Br J Pharmacol

authors

Feng W,Song Y,Chen C,Lu ZZ,Zhang Y

doi

10.1111/j.1476-5381.2009.00558.x

subject

Has Abstract

pub_date

2010-04-01 00:00:00

pages

1598-607

issue

8

eissn

0007-1188

issn

1476-5381

pii

BPH558

journal_volume

159

pub_type

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