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* Junior Research Group Molecular Infection Biology, and
Division of Molecular Infection Biology, Research Center Borstel, Borstel, Germany;
Intractable Disease Research Center, Tokyo Medical University, Tokyo, Japan;
Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Honcho Kawaguchi, Saitama, Japan; Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Nabeshima, Saga, Japan;
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Ontario Cancer Institute and Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Canada; and
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Department of Inflammation Research, Amgen, Inc., Thousand Oaks, CA 91320
IL-12 is a potent inducer of IFN-
production and promotes a protective cell-mediated immune response after Mycobacterium tuberculosis infection. Recently, the IL-12-related cytokine IL-27 was discovered, and WSX-1 was identified as one component of the IL-27R complex. To determine the functional significance of IL-27/WSX-1 during tuberculosis, we analyzed the course of infection and the immune response in WSX-1-KO mice after aerosol infection with M. tuberculosis. In the absence of WSX-1, an increased production of the proinflammatory cytokines TNF and IL-12p40 resulted in elevated CD4+ T cell activation and IFN- production, which enhanced macrophage effector functions and reduced bacterial loads. This is the first occasion of a selectively gene-deficient mouse strain showing higher levels of protective immunity against M. tuberculosis infection than wild-type mice. However, a concomitantly increased chronic inflammatory response also accelerated death of infected WSX-1-KO mice. In vitro, IL-27 induced STAT3 phosphorylation and inhibited TNF and IL-12 production in activated peritoneal macrophages, indicating a novel feedback mechanism by which IL-27 can modulate excessive inflammation. In conclusion, IL-27 both prevents optimal antimycobacterial protection and limits the pathological sequelae of chronic inflammation.
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