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 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 (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 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.
Brieland
J K
JK
Department of Chemotherapy, Schering Plough Research Institute, Kenilworth, New Jersey, USA. joan.brieland@spcorp.com
Jackson
C
C
Hurst
S
S
Loebenberg
D
D
Muchamuel
T
T
Debets
R
R
Kastelein
R
R
Churakova
T
T
Abrams
J
J
Hare
R
R
O'Garra
A
A
D000818:Animals; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000235:genetics; D020382:Interleukin-18 / Q000235:genetics / Q000502:physiology*; D007877:Legionnaires' Disease / Q000276:immunology*; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D051379:Mice
D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma