IL-12 can alleviate Th17-mediated allergic lung inflammation through induction of pulmonary IL-10 expression.
Interleukin (IL)-12 has been shown to suppress T helper type 2 (Th2)-induced pathogenesis that is associated with allergic asthma, largely through interferon (IFN)-gamma production. We have recently shown that in the absence of T-bet, the major regulator of IFN-gamma expression, allergic lung inflammation is primarily associated with IL-17-associated recruitment of neutrophils into the pulmonary tract of mice. In the absence of T-bet, exogenous IL-12 was still able to suppress neutrophilic infiltration and to diminish levels of IL-17, IL-23, and IL-23R, as well as retinoic acid-related orphan receptor gamma t, the transcriptional regulator of the Th17 pathway. The same effects were observed in T-bet(-/-) IFN-gamma(-/-) double knockout mice, showing an IFN-gamma-independent effect of IL-12 in this model. IL-10 expression in the lungs of T-bet-deficient mice was significantly increased after IL-12 treatment, and inoculation of anti-IL-10R mAb completely reversed the ability of IL-12 to suppress histological inflammation, recruitment of inflammatory cell subsets into the lung, bronchiole hyperresponsiveness, and IL-17 production. We conclude that Th17-mediated allergic lung inflammation that becomes dominant in the absence of effective IFN-gamma signaling can be effectively suppressed by IL-12 through an IL-10-dependent mechanism.
Durrant
D M
DM
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
Metzger
D W
DW
D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D007378:Interleukins; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma