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J. Biol. Chem. 278 (24): 21751-21760

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Histamine Antagonizes Tumor Necrosis Factor (TNF) Signaling by Stimulating TNF Receptor Shedding from the Cell Surface and Golgi Storage Pool*

Jun Wang {ddagger}, Rafia S. Al-Lamki {ddagger}, Hui Zhang {ddagger}, Nancy Kirkiles-Smith §, Mary Lou Gaeta §, Sathia Thiru ¶, Jordan S. Pober §, and John R. Bradley {ddagger} ||

{ddagger} Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Box 157, Hills Road, Cambridge CB2 2QQ, United Kingdom
Department of Pathology, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Box 157, Hills Road, Cambridge CB2 2QQ, United Kingdom
§ Interdepartmental Program in Vascular Biology and Transplantation, The Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06511

Abstract: Tumor necrosis factor (TNF) activates pro-inflammatory functions of vascular endothelial cells (EC) through binding to receptor type 1 (TNFR1) molecules expressed on the cell surface. The majority of TNFR1 molecules are localized to the Golgi apparatus. Soluble forms of TNFR1 (as well as of TNFR2) can be shed from the EC surface and inhibit TNF actions. The relationships among cell surface, Golgi-associated, and shed forms of TNFR1 are unclear. Here we report that histamine causes transient loss of surface TNFR1, TNFR1 shedding, and mobilization of TNFR1 molecules from the Golgi in cultured human EC. The Golgi pool of TNFR1 serves both to replenish cell surface receptors and as a source of shed receptor. Histamine-induced shedding is blocked by TNF-{alpha} protease inhibitor, an inhibitor of TNF-{alpha}-converting enzyme, and through the H1 receptor via a MEK-1/p42 and p44 mitogen-activated protein kinase pathway. Cultured EC with histamine-induced surface receptor loss become transiently refractory to TNF. Histamine injection into human skin engrafted on immunodeficient mice similarly caused shedding of TNFR1 and diminished TNF-mediated induction of endothelial adhesion molecules. These results both clarify relationships among TNFR1 populations and reveal a novel anti-inflammatory activity of histamine.

Received for publication December 12, 2002. Revision received March 18, 2003.

* This work was supported by grants from the National Kidney Research Fund (United Kingdom), Medical Research Council, and the National Institutes of Health. 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: Dept. of Medicine, University of Cambridge, Addenbrooke's Hospital, Box 157, Level 5, Hills Rd., Cambridge CB2 2QQ, UK. Fax: 0-11-44-1223-586506; E-mail: john.bradley{at}addenbrookes.nhs.uk.

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