Immunomodulatory role of endogenous interleukin-18 in gamma interferon-mediated resolution of replicative Legionella pneumophila lung infection

The in vivo role of endogenous interleukin-18 (IL-18) in modulating gamma i nterferon (IFN-gamma)-mediated resolution of replicative Legionella pneumop hila lung infection aas assessed using a murine model of Legionnaires' dise ase. Intratracheal inoculation of A/J mice with virulent bacteria (10(6) 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 demon strated 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 adminis tration of a monoclonal antibody (MAb) to the IL-18 receptor (anti-IL-18R M Ab) prior to L. pneumophila infection inhibited induction of intrapulmonary IFN-gamma production but did not significantly alter resolution of replica tive 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 resulte d in enhanced intrapulmonary growth of the bacteria within 5 days postinfec tion. 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. pneumop hila and that together with IL-12, IL-18 regulates intrapulmonary growth of the bacteria.