HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/R1376    most recent 90962.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Sánchez-Lemus, E. Articles by Saavedra, J. M. Search for Related Content PubMed PubMed Citation Articles by Sánchez-Lemus, E. Articles by Saavedra, J. M.

INFLAMMATION, CYTOKINES, NEUROIMMUNE INTERACTIONS

Angiotensin II AT₁ blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen

Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland

Submitted 26 November 2008 ; accepted in final form 16 February 2009

ANG II AT₁ receptor blockade reduces inflammation in hypertension. To determine whether ANG II AT₁ receptor blockers (ARBs) influence the innate immune inflammatory response in normotensive rats, we studied rat plasma and spleen after a 3-day subcutaneous pretreatment with the ARB candesartan followed by a single dose of the bacterial endotoxin LPS (50 µg/kg ip). Peripheral administration of LPS to rodents produced a generalized inflammatory response with increased release of TNF-, IL-1β, and IL-6 into the circulation. Candesartan pretreatment reduced the LPS-induced release of TNF-, IL-1β, and IL-6 into the circulation. The red pulp of rat spleen expressed large numbers of AT₁ receptors and the LPS receptors Toll-like receptor 4 and CD14. Candesartan administration significantly blocked AT₁ receptors. The ARB reduced the LPS-induced upregulation of CD14 gene expression; expression of TNF- and IL-6 mRNA and protein; expression of IL-1β and IB- mRNA; COX-2 mRNA and protein expression and PGE₂ concentration; inducible nitric oxide synthase (iNOS) gene and protein expression and iNOS activity; and Nox2 gene expression and 8-isoprostane levels. In addition, candesartan reduced the CD14 protein expression in saline- and LPS-treated rats. Our results suggest that AT₁ receptors are essential for the development of the full innate immune response to bacterial endotoxin. The ARB decreased the general peripheral inflammatory reaction to LPS and partially decreased the inflammatory response in the spleen. An unrestricted innate immune response to the bacterial endotoxin may have deleterious effects for the organism and may lead to development of chronic inflammatory disease. We postulate that ARBs may have therapeutic effects on inflammatory conditions.

CD14; cyclooxygenase-2; NAPDH oxidase; inducible nitric oxide synthase; proinflammatory cytokines