Chlamydia trachomatis mouse pneumonitis lung infection in IL-18 and IL-12 knockout mice: IL-12 is dominant over IL-18 for protective immunity.
BACKGROUND
Interferon (IFN)-gamma is a key to protective immunity against a variety of intracellular bacterial infections, including Chlamydia trachomatis. Interleukin (IL)-18, a recently identified Th1 cytokine, together with IL-12 is a strong stimulator for IFN-gamma production. We investigated the relative roles of IL-18 and IL- 12 in protective immunity to C. trachomatis mouse pneumonitis (MoPn) infection using gene knockout (KO) and wild-type (WT) mice.


METHODS
Mice were intranasally infected with C. trachomatis MoPn and protective immunity was assessed among groups of mice by daily body weight changes, lung growth of MoPn, and histopathological appearances at day 10 postinfection. The corresponding immune responses for each group of mice at the same postinfection time point were evaluated by measuring antigen-specific antibody isotype responses and cytokine profiles.


RESULTS
Our results showed that IL-18 deficiency had little or no influence on clearance of MoPn from the lung, although KO mice exhibited slightly more severe inflammatory reactions in lung tissues, as well as reduced systemic and local IFN-gamma production, compared with WT mice. Results with IL-18 KO mice were in sharp contrast to those observed with IL-12 KO mice that showed substantially reduced clearance of MoPn from the lungs, substantial reductions of antigen-specific systemic and lung IFN-gamma production, decreased ratio of MoPn-specific immunoglobulin G (IgG)2a/IgG1, and severe pathological changes in the lung with extensive polymorphonuclear, instead of mononuclear, cell infiltration. Exogenous IL-12 or IL-18 was able to increase IFN-gamma production in IL-18 KO mice; whereas, only exogenous IL-12, but not IL-18, enhanced IFN-gamma production in IL-12 KO mice. Caspase-1 is the key protease for activation of IL-18 precursor into the bioactive form, and caspase-1 KO mice also displayed similar bacterial clearance and body weight loss to that in WT mice at early stages of MoPn infection. This further confirmed that IL-18 was not essential for host defense against chlamydia infection.


CONCLUSIONS
These results suggest that IL-12, rather than IL-18, plays the dominant role in the development of protective immunity against chlamydia lung infection, although both cytokines are involved in the in vivo regulation of IFN-gamma production.
Lu
H
H
University of British Columbia, Centre for Disease Control, Vancouver, Canada.
Yang
X
X
Takeda
K
K
Zhang
D
D
Fan
Y
Y
Luo
M
M
Shen
C
C
Wang
S
S
Akira
S
S
Brunham
R C
RC
D000818:Animals; D001835:Body Weight; D002478:Cells, Cultured; D002690:Chlamydia Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002692:Chlamydia trachomatis / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007109:Immunity; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000378:metabolism
D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma