Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes

Autor: Julius Benicky, Enrique Sanchez-Lemus, Juan Wang, Juan M. Saavedra, Martina Orecna, Tao Pang
Rok vydání: 2012
Předmět:
Lipopolysaccharides
Lipopolysaccharide
Physiology
Blotting
Western
Peroxisome proliferator-activated receptor
Electrophoretic Mobility Shift Assay
Inflammation
Real-Time Polymerase Chain Reaction
urologic and male genital diseases
Benzoates
Article
Monocytes
chemistry.chemical_compound
Immunity
Cell Line
Tumor
Internal Medicine
medicine
Humans
Telmisartan
cardiovascular diseases
Receptor
chemistry.chemical_classification
Innate immune system
Angiotensin II receptor type 1
Base Sequence
business.industry
Immunity
Innate
female genital diseases and pregnancy complications
PPAR gamma
chemistry
Immunology
Benzimidazoles
medicine.symptom
DNA Probes
Cardiology and Cardiovascular Medicine
business
Angiotensin II Type 1 Receptor Blockers
hormones
hormone substitutes
and hormone antagonists
medicine.drug
Zdroj: Journal of Hypertension. 30:87-96
ISSN: 0263-6352
DOI: 10.1097/hjh.0b013e32834dde5f
Popis: 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-γ (PPARγ)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPARγ-stimulating activity.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. PPARγ activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPARγ gene silencing.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-κB activation and reactive oxygen species formation. In THP-1 cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-α, inhibitor of κB-α, 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 PPARγ 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 PPARγ antagonism and PPARγ gene silencing. Anti-inflammatory effects of ARBs correlated with their PPARγ agonist potency.Our observations demonstrate that in human monocytes, ARBs inhibit the LPS-induced pro-inflammatory response to a major extent through the PPARγ activation pathway and may be beneficial for the treatment of cardiovascular and metabolic disorders in which inflammation plays a major role.
Databáze: OpenAIRE
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