The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis

C Hölscher, A Hölscher, D Ruckerl… - The Journal of …, 2005 - journals.aai.org
C Hölscher, A Hölscher, D Ruckerl, T Yoshimoto, H Yoshida, T Mak, C Saris, S Ehlers
The Journal of Immunology, 2005journals.aai.org
IL-12 is a potent inducer of IFN-γ 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 …
Abstract
IL-12 is a potent inducer of IFN-γ 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-γ 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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