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-

Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor. Although peroxisome proliferator-activated receptoractivators 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 receptorantagonist, peroxisome proliferatoractivated receptormay 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 proteinsites 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 TNFex vivo. These data suggest that telmisartan may attenuate inflammatory process induced by TNFin addition to the blockade of angiotensin II type 1 receptor. Because both TNFand 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: 00-00.)