Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts.

Academic Article


  • We investigated the expression of the proinflammatory cytokine interleukin (IL)-17 in cardiac fibroblasts and its induction by high glucose (HG). Our results show that primary mouse cardiac fibroblasts (mCFs) secrete low basal levels of IL-17 and that HG (25 mM D-glucose) as opposed to low glucose (5 mM D-glucose + 20 mM mannitol) significantly enhances its secretion. HG induces IL-17 mRNA expression by both transcriptional and posttranscriptional mechanisms. HG induces phosphoinositide 3- kinase [PI3K; inhibited by adenoviral (Ad).dominant negative (dn)PI3Kp85], Akt (inhibited by Ad.dnAkt1), and ERK (inhibited by PD-98059) activation and induces IL-17 expression via PI3K-->Akt-->ERK-dependent signaling. Moreover, mCFs express both IL-17 receptors A and C, and although IL-17RA is upregulated, HG fails to modulate IL-17RC expression. Furthermore, IL-17 stimulates net collagen production by mCFs. Pretreatment with the phytoalexin resveratrol blocks HG-induced PI3K-, Akt-, and ERK-dependent IL-17 expression. These results demonstrate that 1) cardiac fibroblasts express IL-17 and its receptors; 2) HG upregulates IL-17 and IL-17RA, suggesting a positive amplification loop in IL-17 signaling in hyperglycemia; 3) IL-17 enhances net collagen production; and 4) resveratrol can inhibit these HG-induced changes. Thus, in hyperglycemic conditions, IL-17 may potentiate myocardial inflammation, injury, and remodeling through autocrine and paracrine mechanisms, and resveratrol has therapeutic potential in ameliorating this effect.
  • Authors


  • Animals, Cardiovascular Agents, Cell Culture Techniques, Cells, Cultured, Collagen, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Fibroblasts, Flavonoids, Glucose, Hyperglycemia, Interleukin-17, Male, Mice, Mice, Inbred C57BL, Myocardium, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, RNA, Messenger, Receptors, Interleukin, Receptors, Interleukin-17, Resveratrol, Signal Transduction, Stilbenes, Time Factors, Up-Regulation
  • Digital Object Identifier (doi)

    Author List

  • Venkatachalam K; Mummidi S; Cortez DM; Prabhu SD; Valente AJ; Chandrasekar B
  • Start Page

  • H2078
  • End Page

  • H2087
  • Volume

  • 294
  • Issue

  • 5