Candesartan inhibits Toll-like receptor expression and activity both in vitro and in vivo.
BACKGROUND
Toll-like receptors play an important role in the innate immune system and are found to be crucial in severe diseases like sepsis, atherosclerosis, and arthritis. TLR2 and TLR4 expression is upregulated in the inflammatory diseases. Angiotensin II in addition to stimulating vasoconstriction also induces an increase in ROS and a proinflammatory phenotype via AT(1)R. Angiotensin II type-1 receptor blocker (ARB), widely used as an antihypertensive drug, has been reported to also have anti-inflammatory effects. Thus, we investigated whether an ARB exerts anti-inflammatory effects via inhibiting TLR2 and TLR4 expression.


RESULTS
Monocytes were isolated from healthy human volunteers and treated with the synthetic lipoprotein Pam3CSK4 or LPS in the absence or presence of candesartan. Pretreatment of human monocytes with candesartan significantly decreased Pam3CSK4 or LPS induced TLR2 and TLR4 expression of both mRNA and protein levels (P<0.05 vs. control) along with decrease in the activity of NF-kappaB and the expression of IL-1beta, IL-6, TNF-alpha, and MCP-1. Furthermore, candesartan treated mice show decreased TLR2 and TLR4 expression compared to vehicle control mice.


CONCLUSIONS
Pam3CSK4 and LPS induced TLR2 and TLR4 expression at mRNA and protein levels are inhibited by candesartan both in vitro and in vivo. Thus, we define a novel pathway by which candesartan could induce anti-inflammatory effects.
Dasu
Mohan R
MR
Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, Sacramento, CA 95817, United States.
Riosvelasco
Andrea C
AC
Jialal
Ishwarlal
I
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation; D055666:Lipopeptides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D010641:Phenotype; D017382:Reactive Oxygen Species; D013777:Tetrazoles / Q000494:pharmacology*; D051193:Toll-Like Receptors / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D051193:Toll-Like Receptors; C081643:candesartan