IL-12 can alleviate Th17-mediated allergic lung inflammation through induction of pulmonary IL-10 expression

Mucosal Immunol. 2010 May;3(3):301-11. doi: 10.1038/mi.2010.9. Epub 2010 Mar 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Asthma / genetics
  • Asthma / immunology*
  • Asthma / metabolism
  • Asthma / pathology
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology*
  • Interleukin-10 / metabolism
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology*
  • Interleukin-12 / metabolism
  • Interleukins / immunology
  • Interleukins / metabolism
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Neutrophil Infiltration / genetics
  • Neutrophil Infiltration / immunology
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Pneumonia / genetics
  • Pneumonia / immunology*
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism
  • Th2 Cells / pathology

Substances

  • Interleukins
  • Interleukin-10
  • Interleukin-12
  • Interferon-gamma