Exp Mol Med.
2010 Aug;42(8):533-546. 10.3858/emm.2010.42.8.054.
IL-12-STAT4-IFN-gamma axis is a key downstream pathway in the development of IL-13-mediated asthma phenotypes in a Th2 type asthma model
- Affiliations
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- 1Department of Life Science, Division of Molecular and Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 790-784, Korea. juinea@postech.ac.kr
- 2Division of Allergy and Clinical Immunology, Asthma and Allergy Center, Johns Hopkins University, MD, USA.
- 3Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, USA.
- 4Deparment of Allergy and Clinical Immunology, Sungkyunkwan University College of Medicine, Seoul 135-710, Korea.
- KMID: 1104380
- DOI: http://doi.org/10.3858/emm.2010.42.8.054
Abstract
- IL-4 and IL-13 are closely related cytokines that are produced by Th2 cells. However, IL-4 and IL-13 have different effects on the development of asthma phenotypes. Here, we evaluated downstream molecular mechanisms involved in the development of Th2 type asthma phenotypes. A murine model of Th2 asthma was used that involved intraperitoneal sensitization with an allergen (ovalbumin) plus alum and then challenge with ovalbumin alone. Asthma phenotypes, including airway-hyperresponsiveness (AHR), lung inflammation, and immunologic parameters were evaluated after allergen challenge in mice deficient in candidate genes. The present study showed that methacholine AHR and lung inflammation developed in allergen-challenged IL-4-deficient mice but not in allergen-challenged IL-13-deficient mice. In addition, the production of OVA-specific IgG2a and IFN-gamma-inducible protein (IP)-10 was also impaired in the absence of IL-13, but not of IL-4. Lung-targeted IFN-gamma over-expression in the airways enhanced methacholine AHR and non-eosinophilic inflammation; in addition, these asthma phenotypes were impaired in allergen-challenged IFN-gamma-deficient mice. Moreover, AHR, non-eosinophilic inflammation, and IFN-gamma expression were impaired in allergen-challenged IL-12Rbeta2- and STAT4-deficient mice; however, AHR and non-eosinophilic inflammation were not impaired in allergen-challenged IL-4Ralpha-deficient mice, and these phenomena were accompanied by the enhanced expression of IL-12 and IFN-gamma. The present data suggest that IL-13-mediated asthma phenotypes, such as AHR and non-eosinophilic inflammation, in the Th2 type asthma are dependent on the IL-12-STAT4-IFN-gamma axis, and that these asthma phenotypes are independent of IL-4Ralpha-mediated signaling.
Keyword
MeSH Terms
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Allergens/immunology
Animals
Asthma/complications/*immunology/pathology/physiopathology
Bronchial Hyperreactivity/complications/immunology/pathology
Disease Models, Animal
Interferon-gamma/*immunology
Interleukin-12/*immunology
Interleukin-12 Receptor beta 2 Subunit/metabolism
Interleukin-13/deficiency/*immunology
Interleukin-4/deficiency
Methacholine Chloride
Mice
Mice, Transgenic
Models, Immunological
Organ Specificity
Pneumonia/complications/immunology/pathology
Receptors, Cell Surface/metabolism
STAT4 Transcription Factor/*metabolism
Signal Transduction/*immunology
Th2 Cells/*immunology
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