Submitted on November 26, 2007
Accepted on February 27, 2008
Resveratrol inhibits high glucose-induced PI3K/AKT/ERK-dependent
interleukin-17 expression in primary mouse cardiac fibroblasts
Kaliyamurthi Venkatachalam1, Srinivas Mummidi2, Dolores M Cortez1, Sumanth D. Prabhu3, Anthony J Valente4, and Bysani Chandrasekar5*
1 Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
2 Medicine, University of Texas HSC, San Antonio, Texas, United States
3 Dept of Medicine, University of Louisville, Louisville, Kentucky, United States
4 Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States; San Antonio, Texas, United States
5 Medicine/Cardiology, UT Health Scence Center, San Antonio, United States
* To whom correspondence should be addressed. E-mail: chandraseka{at}uthscsa.edu.
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 (mCF) secrete low basal levels of IL-17 and that high glucose (25 mM D-glucose) as opposed to low glucose (LG; 5 mM D-glucose + 20 mM mannitol) significantly enhances its secretion. HG induces IL-17 mRNA expression by both transcriptional and post-transcriptional mechanisms. HG induces PI3K (inhibited by Ad.dnPI3Kp85), Akt (inhibited by Ad.dnAkt1) and ERK (inhibited by PD98059) activation, and induces IL-17 expression via PI3K
AktERK-dependent signaling. Moreover, mCF express both IL-17 receptors A and C, and while IL-17RA is upregulated, HG fails to modulate IL-17RC expression. Furthermore, IL-17 stimulates net collagen production by mCF. Pre-treatment with the phytoalexin resveratrol blocks HG-induced PI3K-, Akt-, and ERK-dependent IL-17 expression. These results demonstrate that (i) cardiac fibroblasts express IL-17 and its receptors, (ii) high glucose upregulates IL-17 and IL-17RA, suggesting a positive amplification loop in IL-17 signaling in hyperglycemia, (iii) IL-17 enhances net collagen production, and (iv) 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.
