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Infection and Immunity, December 2000, p. 6567-6573, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Immunomodulatory Role of Endogenous Interleukin-18 in Gamma Interferon-Mediated Resolution of Replicative Legionella pneumophila Lung Infection

Joan K. Brieland,1,* Craig Jackson,1 Steve Hurst,2 David Loebenberg,1 Tony Muchamuel,2 Reno Debets,2 Rob Kastelein,2 Tatyana Churakova,2 John Abrams,2 Roberta Hare,1 and Anne O'Garra2

Department of Chemotherapy, Schering Plough Research Institute, Kenilworth, New Jersey,1 and DNAX Research Institute, Palo Alto, California2

Received 25 May 2000/Returned for modification 16 July 2000/Accepted 22 August 2000

The in vivo role of endogenous interleukin-18 (IL-18) in modulating gamma interferon (IFN-gamma )-mediated resolution of replicative Legionella pneumophila lung infection was assessed using a murine model of Legionnaires' disease. Intratracheal inoculation of A/J mice with virulent bacteria (106 L. pneumophila organisms per mouse) resulted in induction of IL-18 protein in bronchoalveolar lavage fluid (BALF) and intrapulmonary expression of IL-18 mRNA. Real-time quantitative RT-PCR analysis of infected lung tissue demonstrated that induction of IL-18 in BALF preceded induction of IL-12 and IFN-gamma mRNAs in the lung. Blocking intrapulmonary IL-18 activity by administration of a monoclonal antibody (MAb) to the IL-18 receptor (anti-IL-18R MAb) prior to L. pneumophila infection inhibited induction of intrapulmonary IFN-gamma production but did not significantly alter resolution of replicative L. pneumophila lung infection. In contrast, blocking endogenous IL-12 activity by administration of anti-IL-12 MAb) alone or in combination with anti-IL-18R MAb inhibited induction of intrapulmonary IFN-gamma and resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection. Taken together, these results demonstrate that IL-18 plays a key role in modulating induction of IFN-gamma in the lung in response to L. pneumophila and that together with IL-12, IL-18 regulates intrapulmonary growth of the bacteria.

* Corresponding author. Mailing address: Schering Plough Research Institute, 2015 Galloping Hill Rd., K15-B432 4800, Kenilworth, NJ 07033. Phone: (908) 740-3147. Fax: (908) 740-3918. E-mail: joan.brieland{at}spcorp.com.

Infection and Immunity, December 2000, p. 6567-6573, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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