Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-gamma activation in human monocytes.
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Pang T, Benicky J, Wang J, Orecna M, Sanchez-Lemus E, Saavedra JM
Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-gamma activation in human monocytes.
J Hypertens. 2012 Jan;30(1):87-96. doi: 10.1097/HJH.0b013e32834dde5f.
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- 22124178 [ View in PubMed]
- Abstract
OBJECTIVE: Angiotensin II type 1 receptor (AT1) blockers (ARBs) reduce the bacterial endotoxin lipopolysaccharide (LPS)-induced innate immune response in human circulating monocytes expressing few AT1. To clarify the mechanisms of anti-inflammatory effects of ARBs with different peroxisome proliferator-activated receptor-gamma (PPARgamma)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPARgamma-stimulating activity. METHODS: Human circulating monocytes and monocytic THP-1 (human acute monocytic leukemia cell line) cells were exposed to 50 ng/ml LPS with or without pre-incubation with telmisartan. AT1 mRNA and protein expressions were determined by real-time PCR and membrane receptor binding assay, respectively. The expression of pro-inflammatory factors was determined by real-time PCR, western blot analysis and ELISA. PPARgamma activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPARgamma gene silencing. RESULTS: In human monocytes, telmisartan significantly attenuated the LPS-induced expression of pro-inflammatory factors, the release of pro-inflammatory cytokines and prostaglandin E2, nuclear factor-kappaB activation and reactive oxygen species formation. In THP-1 cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-alpha, inhibitor of kappaB-alpha, monocyte chemotactic protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 gene expression and MCP-1-directed migration. Telmisartan also stimulated the expression of the PPARgamma target genes cluster of differentiation 36 and ATP-binding cassette subfamily G member 1 in monocytes. The anti-inflammatory effects of telmisartan were prevented by both PPARgamma antagonism and PPARgamma gene silencing. Anti-inflammatory effects of ARBs correlated with their PPARgamma agonist potency. CONCLUSION: Our observations demonstrate that in human monocytes, ARBs inhibit the LPS-induced pro-inflammatory response to a major extent through the PPARgamma activation pathway and may be beneficial for the treatment of cardiovascular and metabolic disorders in which inflammation plays a major role.