Inhibition of Tumor Necrosis Factor-–Induced Interleukin-6 Expression by Telmisartan Through Cross-Talk of Peroxisome Proliferator-Activated Receptor- With Nuclear Factor B and CCAAT/Enhancer-Binding Protein-

Abstract—Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor-. Although peroxisome proliferator-activated receptor- activators have been shown to have an anti-inflammatory effect, such as inhibition of cytokine production, it has not been determined whether telmisartan has such effects. We examined whether telmisartan inhibits expression of interleukin-6 (IL-6), a proinflammatory cytokine, in vascular smooth muscle cells. Telmisartan, but not valsartan, attenuated IL-6 mRNA expression induced by tumor necrosis factor- (TNF-). Telmisartan decreased TNF-–induced IL-6 mRNA and protein expression in a dose-dependent manner. Because suppression of IL-6 mRNA expression was prevented by pretreatment with GW9662, a specific peroxisome proliferator-activated receptor- antagonist, peroxisome proliferator-activated receptor- may be involved in the process. Telmisartan suppressed IL-6 gene promoter activity induced by TNF-. Deletion analysis suggested that the DNA segment between 150 bp and 27 bp of the IL-6 gene promoter that contains nuclear factor B and CCAAT/enhancer-binding protein- sites was responsible for telmisartan suppression. Telmisartan attenuated TNF-–induced nuclear factor B – and CCAAT/enhancer-binding protein-– dependent gene transcription and DNA binding. Telmisartan also attenuated serum IL-6 level in TNF-–infused mice and IL-6 production from rat aorta stimulated with TNF- ex vivo. These data suggest that telmisartan may attenuate inflammatory process induced by TNF- in addition to the blockade of angiotensin II type 1 receptor. Because both TNF- and angiotensin II play important roles in atherogenesis through enhancement of vascular inflammation, telmisartan may be beneficial for treatment of not only hypertension but also vascular inflammatory change. (Hypertension. 2009;53