title: Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts.
abstract: 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.affiliation: Department of Veterans' Affairs, South Texas Veterans Health Care System-Audie L. Murphy Division, San Antonio, TX 78229-3900, USA.
authors.forename: Kaliyamurthi
authors.initials: K
authors.lastname: Venkatachalam
authors.forename: Srinivas
authors.initials: S
authors.lastname: Mummidi
authors.forename: Dolores M
authors.initials: DM
authors.lastname: Cortez
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000201:enzymology / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D002317:Cardiovascular Agents; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D005947:Glucose; D020381:Interleukin-17; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D000077185:Resveratrol; D013267:Stilbenes; C491673:Il17ra protein, mouse; C508527:Il17rc protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one