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

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-7 antagonist, peroxisome proliferatoractivated 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-βdependent 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.