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 tracho matis. Interleukin (IL)-18, a recently identified Th1 cytokine, together wi th IL-12 is a strong stimulator for IFN-gamma production. We investigated t he relative roles of IL-18 and IL-12 in protective immunity to C. trachomat is mouse pneumonitis (MoPn) infection using gene knockout (KO) and wild-typ e (WT) mice. Materials and Methods: Mice were intranasally infected with C, trachomatis MoPn and protective immunity was assessed among groups of mice by daily bod y 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 anti gen-specific antibody isotype responses and cytokine profiles. Results: Our results showed that IL-18 deficiency had little or no influenc e on clearance of MoPn from the lung, although KO mice exhibited slightly m ore severe inflammatory reactions in lung tissues, as well as reduced syste mic 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 decr eased ratio of MoPn-specific immunoglobulin G (IgG)2a/IgG1, and severe path ological changes in the lung with extensive polymorphonuclear, instead of m ononuclear, cell infiltration. Exogenous IL-12 or IL-18 was able to increas e 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 th e key protease for activation of IL-18 precursor into the bioactive form, a nd caspase-1 KO mice also displayed similar bacterial clearance and body we ight loss to that in WT mice at early stages of MoPn infection. This furthe r 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 regulat ion of IFN-gamma production.