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J Biol Chem, Vol. 275, Issue 20, 14903-14909, May 19, 2000

Involvement of the Acute Phase Protein alpha 1-Acid Glycoprotein in Nonspecific Resistance to a Lethal Gram-negative Infection*

Tino HochepiedDagger §, Wim Van MolleDagger , Franklin G. Berger||, Heinz Baumann**, and Claude LibertDagger Dagger Dagger

From the Dagger  Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, 9000 Ghent, Belgium, the || Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208, and the ** Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263

Resistance to Gram-negative infection can be induced by pretreating animals with several agents such as turpentine and interleukin (IL)-1. Because these agents are powerful inducers of acute phase proteins, we wondered whether these proteins, more particularly alpha 1-acid glycoprotein (alpha 1-AGP), are involved in nonspecific resistance to infection. Turpentine and IL-1 protect completely against a lethal challenge of Klebsiella pneumoniae when given 48 and 12-48 h before the challenge, respectively. alpha 1-AGP induction in the serum reached peak values 48 h after turpentine and 12-48 h after IL-1 injection. Administration of alpha 1-AGP, 2 h before a challenge of K. pneumoniae, significantly increased the survival. Numbers of bacteria cultured from blood and organs were significantly lower in mice pretreated with a protective dose of turpentine, IL-1, or alpha 1-AGP. These data suggest that alpha 1-AGP is a possible mediator in turpentine- or IL-1-induced protection because time points of maximal induction of alpha 1-AGP by turpentine or IL-1 and of optimal protection by alpha 1-AGP coincide. Transgenic overexpression of rat alpha 1-AGP protected mice from a K. pneumoniae infection. Bacterial counts in blood and organs were significantly lower in transgenic mice, and only in control mice were large necrotic areas, apoptosis, and blood clots observed in the spleen. Our data suggest that alpha 1-AGP prevents Gram-negative infections and may be an essential component in nonspecific resistance to infection.

* This work was supported in part by the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen Grant G023698N Algemene Spaar en Lijfrentekas and the Interuniversitaire Attractiepolen.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Fellow with the Vlaams Instituut voor de Bevordering van het Wetenschappelijk-technologisch Onderzoek in de Industrie.

Postdoctoral researcher with the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen.

Dagger Dagger To whom correspondence should be addressed: Dept. of Molecular Biology, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium. Tel.: 32-9264-8770; Fax: 32-9264-5348; E-mail: claude@dmb.rug.ac.be.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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