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Infection and Immunity, October 2002, p. 5715-5720, Vol. 70, No. 10
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.10.5715-5720.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Combined Treatment with Interleukin-12 and Indomethacin Promotes Increased Resistance in BALB/c Mice with Established Leishmania major Infections

Jian Li, Udaikumar M. Padigel, Phillip Scott, and Jay P. Farrell^*

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Received 6 May 2002/ Returned for modification 29 June 2002/ Accepted 13 July 2002

Following infection of susceptible BALB/c mice with Leishmania major, early production of interleukin-4 (IL-4) is associated with the development of a nonprotective Th2 response and the development of progressive disease. Treatment of mice with IL-12 at the time of infection can promote the activation of a protective Th1 response; however, IL-12 treatment of mice with established infections has little effect on the progress of lesion development. This may be due to a down-regulation of the IL-12 receptor ß2 chain (IL-12Rß2) that accompanies the expansion of IL-4-producing Th2 cells. We have examined whether prostaglandins function to regulate in vivo responsiveness to IL-12. Mice treated with indomethacin are responsive to treatment with exogenous IL-12 through at least the first 2 weeks of infection and, unlike control mice treated with IL-12, develop an enhanced Th1-type response associated with increased enhanced resistance to infection. Cells from indomethacin-treated mice also exhibit enhanced production of gamma interferon (IFN-) following in vitro stimulation with IL-12. Although in vivo indomethacin treatment did not appear to influence IL-12 production in infected mice, cells from indomethacin-treated mice did express higher levels of IL-12Rß2, suggesting that prostaglandins may play a role in the loss of IL-12 responsiveness observed during nonhealing L. major infections.

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* Corresponding author. Mailing address: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce St., Philadelphia, PA 19104. Phone: (215) 898-8561. Fax: (215) 573-7023. E-mail: farrellj{at}vet.upenn.edu.

Editor: W. A. Petri, Jr.

Present address: Department of Immunobiology, Centocor, Inc., Malvern, PA 19355.

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Infection and Immunity, October 2002, p. 5715-5720, Vol. 70, No. 10
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.10.5715-5720.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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