Abstract 5249: Telmisartan Manifests Powerful Anti-Inflammatory Effects Beyond Class Effects of Angiotensin II Type 1 Blocker by Inhibiting Tumor Necrosis Factor α-Induced Interleukin 6 Expressions through Peroxisome Proliferator Activated Receptorγ Activation
Objective: Thiazolidinedione, a synthetic of peroxisome proliferator-activated receptor gamma (PPARγ) activators, is an insulin-sensitizer to treat diabetes mellitus and also shown to have an anti-inflammatory effect through transrepression of transcription factors such as NF-κB and AP-1. Telmisartan, an angiotensin (Ang) II type 1 receptor (AT1R) antagonist, was reported to be a partial agonist of PPARγ. We examined whether telmisartan inhibits expression of interleukin-6 (IL-6), a proinflammatory cytokine, in vascular smooth muscle cells (VSMCs) just as thiazolidinediones through transrepression mechanism.
Methods: VSMC derived from the aorta of SD rats was used. IL-6 mRNA and IL-6 protein levels were measured by conventional Northern blot analysis and ELISA, respectively. IL-6 promoter activity was measured by luciferase assay.
Results: Telmisartan (10 μmol/L) but not valsartan (10μmol/L) attenuated IL-6 mRNA expression induced by tumor necrosis factor (TNF)-α (10 ng/ml) by 30 % (n=4, p<0.05). TNFα-induced IL-6 mRNA expression was also suppressed by pioglitazone, one of the thiazolidinediones. ELISA showed that telmisartan partially inhibited IL-6 protein production in the supernatant of TNFα-stimulated VSMC in a dose-dependent manner (about 40% reduction by 20 μmol/L of telmisartan) and completely suppressed AngII (100 nmol/L)-induced IL-6 production. The suppression of TNFα-induced IL-6 mRNA expression by telmisartan was reversed by pretreatment with GW9662, a PPARγ antagonist. Telmisartan suppressed IL-6 gene promoter activity. Deletion analysis of the IL-6 gene promoter indicated that NF-κB and C/EBPβ sites were responsible for the suppression by telmisartan. Gel mobility shift assay showed that telmisartan attenuated TNFα-induced activation of NF-κB and C/EBPβ.
Conclusion: Telmisartan inhibits TNFα-induced IL-6 expression at the transcriptional level through the activation of PPARγ. The transrepression effects of telmisartan on NF-κB and C/EBPβ activity are responsible for the IL-6 suppression. This unique anti-inflammatory effects of telmisartan beyond its class effects as AT1R blocker might make this compound a very powerful inhibitor of atherosclerosis.