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Infection and Immunity, April 1999, p. 1901-1909, Vol. 67, No. 4
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Effects of Interleukin-1 Receptor Antagonist Overexpression on Infection by Listeria monocytogenes

Vera M. Irikura,1 Emmet Hirsch,2 and David Hirsh1,*

Department of Biochemistry and Molecular Biophysics1 and Department of Obstetrics and Gynecology,2 College of Physicians and Surgeons, Columbia University, New York, New York 10032

Received 9 December 1998/Returned for modification 7 January 1999/Accepted 19 January 1999

Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring cytokine whose only known function is the inhibition of interleukin-1 (IL-1). Using a reverse genetic approach in mice, we previously showed that increasing IL-1ra gene dosage leads to reduced survival of a primary listerial infection. In this study, we characterize further the role of endogenously produced IL-1ra and, by inference, IL-1 in murine listeriosis. IL-1ra overexpression inhibits, but does not eliminate, primary immune responses, reducing survival and increasing bacterial loads in the target organs. We demonstrate that IL-1ra functions in the innate immune response to regulate the peak leukocyte levels in the blood, the accumulation of leukocytes at sites of infection, and the activation of macrophages during a primary infection. Reduced macrophage class II major histocompatibility complex expression was observed despite increased gamma interferon (IFN-gamma ) levels, suggesting that IL-1 activity is essential along with IFN-gamma for macrophage activation in vivo. We also show that IL-1ra plays a more limited role during secondary listeriosis, blunting the strength of the delayed-type hypersensitivity response to listerial antigen while not significantly altering cellular immunity to a second infectious challenge. When these results are compared to those for other mutant mice, IL-1ra appears to be unique among the cytokines studied to date in its regulation of leukocyte migration during primary listeriosis.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th St., New York, NY 10032. Phone: (212) 305-3669. Fax: (212) 305-7932. E-mail: dih1{at}columbia.edu.

Infection and Immunity, April 1999, p. 1901-1909, Vol. 67, No. 4
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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