Candesartan reduces the innate immune response to lipopolysaccharide in human monocytes

Objective Inhibition of angiotensin II receptor type 1 (AT(1)) reduces chronic inflammation associated with hypertension. We asked whether AT(1) receptor inhibition would reduce the innate inflammatory response induced by bacterial lipopolysaccharide (LPS). Methods We used unstimulated human circulating monocytes obtained from healthy donors by counterflow centrifugal elutriation. Monocytes were studied in vitro after incubation with LPS (50 ng/ml) with and without 1 mu mol/l candesartan, an AT(1) receptor blocker. Angiotensin II receptor mRNA expression was determined by reverse transcriptase-PCR and receptor binding by autoradiography; inflammatory factor mRNA expression was studied by reverse transcriptase-PCR and cytokine release by ELISA. Results Human monocytes did not express detectable AT(1) receptors, and angiotensin II did not induce inflammatory factor mRNA expression or cytokine release. However, candesartan substantially reduced the LPS-induced expression of the mRNAs for the LPS recognition protein cluster of differentiation 14, the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta and interleukin-6 and the lectin-like oxidized low-density lipoprotein receptor. In addition, candesartan reduced the activation of the nuclear factor kappa B pathway, the tumor necrosis factor alpha and interleukin-6 secretion, and the ROS formation induced by LPS, without affecting the secretion of interleukin-10. Conclusion We hypothesize that the anti-inflammatory effects of candesartan in these cells are likely mediated by mechanisms unrelated to AT(1) receptor blockade. Our results demonstrate that candesartan significantly reduces the innate immune response to LPS in human circulating monocytes. The anti-inflammatory effects of candesartan may be of importance not only in hypertension but also in other inflammatory disorders. J Hypertens 27:2365-2376 (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.