title: Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes.
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-γ (PPARγ)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPARγ-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. PPARγ activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPARγ 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-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.
  
  
  CONCLUSIONS
  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.
authors: Section on Pharmacology, Division of Intramural Research Programs, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA. pangt@mail.nih.gov
authors: Tao
authors: T
authors: Pang
authors: Julius
authors: J
authors: Benicky
authors: Juan
authors: J
authors: Wang
authors: Martina
authors: M
authors: Orecna
authors: Enrique
authors: E
authors: Sanchez-Lemus
authors: Juan M
authors: JM
authors: Saavedra
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015342:DNA Probes; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D047495:PPAR gamma / Q000819:agonists*; D060888:Real-Time Polymerase Chain Reaction; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D015342:DNA Probes; D008070:Lipopolysaccharides; D047495:PPAR gamma; D000077333:Telmisartan