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.