The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis.
IL-12 is a potent inducer of IFN-gamma 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-gamma 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.
Hölscher
Christoph
C
Junior Research Group Molecular Infection Biology, Research Center Borstel, Borstel, Germany. choelscher@fz-borstel.de
Hölscher
Alexandra
A
Rückerl
Dominik
D
Yoshimoto
Takayuki
T
Yoshida
Hiroki
H
Mak
Tak
T
Saris
Christiaan
C
Ehlers
Stefan
S
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics; D053762:Interleukin-12 Subunit p40; D008168:Lung / Q000473:pathology; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010766:Phosphorylation; D021122:Protein Subunits / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016207:Cytokines; D004268:DNA-Binding Proteins; C484747:Il27ra protein, mouse; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D004247:DNA