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J. Biol. Chem., Vol. 278, Issue 45, 45034-45039, November 7, 2003

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Lipopolysaccharide Induces Anandamide Synthesis in Macrophages via CD14/MAPK/Phosphoinositide 3-Kinase/NF-B Independently of Platelet-activating Factor^*

Jie Liu, Sándor Bátkai, Pál Pacher, Judith Harvey-White, Jens A. Wagner, Benjamin F. Cravatt¶, Bin Gao, and George Kunos||

From the Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892, the Department of Medicine, University of Wuerzburg, Wuerzburg 97080, Germany, and the ^¶Scripps Institute, La Jolla, California, 92037

Macrophage-derived endocannabinoids have been implicated in endotoxin (lipopolysaccharide (LPS))-induced hypotension, but the endocannabinoid involved and the mechanism of its regulation by LPS are unknown. In RAW264.7 mouse macrophages, LPS (10 ng/ml) increases anandamide (AEA) levels >10-fold via CD14-, NF-B-, and p44/42-dependent, platelet-activating factor-independent activation of the AEA biosynthetic enzymes, N-acyltransferase and phospholipase D. LPS also induces the AEA-degrading enzyme fatty acid amidohydrolase (FAAH), and inhibition of FAAH activity potentiates, whereas actinomycin D or cycloheximide blocks the LPS-induced increase in AEA levels and N-acyltransferase and phospholipase D activities. In contrast, cellular levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) are unaffected by LPS but increased by platelet-activating factor. LPS similarly induces AEA, but not 2-AG, in mouse peritoneal macrophages where basal AEA levels are higher, and the LPS-stimulated increase in AEA is potentiated in cells from FAAH^-/- as compared with FAAH^+/+ mice. Intravenous administration of 10⁷ LPS-treated mouse macrophages to anesthetized rats elicits hypotension, which is much greater in response to FAAH^-/- than FAAH^+/+ cells and is susceptible to inhibition by SR141716, a cannabinoid CB₁ receptor antagonist. We conclude that AEA and 2-AG synthesis are differentially regulated in macrophages, and AEA rather than 2-AG is a major contributor to LPS-induced hypotension.

Received for publication, June 9, 2003 , and in revised form, August 8, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: National Institute on Alcohol Abuse and Alcoholism, 12420 Parklawn Dr., MSC-8115, Bethesda, MD 20892-8115. Tel.: 301-443-2069; Fax: 301-480-0257; E-mail: gkunos{at}mail.nih.gov.

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