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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 53; no. 5; pp. 798 - 804
• Main Authors: Tian, Qingping, Miyazaki, Ryohei, Ichiki, Toshihiro, Imayama, Ikuyo, Inanaga, Keita, Ohtsubo, Hideki, Yano, Kotaro, Takeda, Kotaro, Sunagawa, Kenji
• Format: Journal Article
• Language: English
• Published: American Heart Association, Inc 01-05-2009
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.108.126656

Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor-γ. Although peroxisome proliferator-activated receptor-γ 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-α (TNF-α). Telmisartan decreased TNF-α–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-γ antagonist, peroxisome proliferator-activated receptor-γ may be involved in the process. Telmisartan suppressed IL-6 gene promoter activity induced by TNF-α. Deletion analysis suggested that the DNA segment between −150 bp and −27 bp of the IL-6 gene promoter that contains nuclear factor κB and CCAAT/enhancer-binding protein-β sites was responsible for telmisartan suppression. Telmisartan attenuated TNF-α–induced nuclear factor κB– and CCAAT/enhancer-binding protein-β–dependent gene transcription and DNA binding. Telmisartan also attenuated serum IL-6 level in TNF-α–infused mice and IL-6 production from rat aorta stimulated with TNF-α ex vivo. These data suggest that telmisartan may attenuate inflammatory process induced by TNF-α in addition to the blockade of angiotensin II type 1 receptor. Because both TNF-α 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.