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

Abstract

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 proliferatoractivated 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 Ϫ150 bp and Ϫ27 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: 798-804.)

Direct Angiotensin II Type 2 Receptor Stimulation Acts Anti-Inflammatory Through Epoxyeicosatrienoic Acid and Inhibition of Nuclear Factor κB

“…10,23,24 Thus, AT 2 R stimulation seems to be able to interfere with signaling cascades coupled to detrimental stimuli, which do not necessarily have to be considered part of the RAS. "Conventional" ARBs seem not to be able to repress cytokine-induced IL6 expression, as shown in this study and very recently by Tian et al 25 Apparently, additional peroxisome proliferator-activated receptor-␥-agonistic properties are necessary for a direct anti-inflammatory action of ARBs by a peroxisome proliferator-activated receptor-␥/ NF-B cross-talk. 25 The molecular mechanism of interference of AT 2 Rcoupled signaling with cytokine-coupled signaling is probably based on interruption of kinase-dependent phosphorylation cascades by dephosphorylation through activated phosphatases.…”

“…"Conventional" ARBs seem not to be able to repress cytokine-induced IL6 expression, as shown in this study and very recently by Tian et al 25 Apparently, additional peroxisome proliferator-activated receptor-␥-agonistic properties are necessary for a direct anti-inflammatory action of ARBs by a peroxisome proliferator-activated receptor-␥/ NF-B cross-talk. 25 The molecular mechanism of interference of AT 2 Rcoupled signaling with cytokine-coupled signaling is probably based on interruption of kinase-dependent phosphorylation cascades by dephosphorylation through activated phosphatases. Such an interference has already been shown for extracellular regulated kinase and signal transducer and activator of transcription signaling and for the deactivation of NF-B.…”

Effect of telmisartan on acute model of inflammation in male Wistar rats: an experimental study

“…TNF-α and angiotensin II play important roles in atherogenesis through enhancement of vascular inflammation. 13 ARBs have been found to decrease TNF-α and IL-6 levels in a dose dependent manner.…”

Effect of telmisartan on selected adipokines, insulin sensitivity, and substrate utilization during insulin-stimulated conditions in patients with metabolic syndrome and impaired fasting glucose

“…In addition, proinflammatory properties of TNFa could be attenuated by telmisartan. Inhibition of TNFa-induced IL6 expression in vascular smooth muscle cells has been reported after telmisartan treatment (37).…”