IL-12-STAT4-IFN-γ axis is a key downstream pathway in the development of IL-13-mediated asthma phenotypes in a Th2 type asthma model

You-Sun Kim,Chun Geun Lee,Seong Gyu Jeon,Zhou Zhu,Yong Song Gho,Seng-Jin Choi,Jun-Pyo Choi,Jack A Elias,Sun-Young Oh,Byung-Jae Lee,Yoon-Keun Kim

doi: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.

Highlights

Asthma is an increasingly common disease that is characterized by airway hyperresponsiveness (AHR) and chronic inflammation and remodeling (Pueringer and Hunninghake, 1992)
Examination of cellularity in bronchoalveolar lavage (BAL) fluids 48 h after the final allergen challenge showed that the IL-13-/mice sensitized with OVA + alum had not developed allergen challenge-induced inflammation, as compared with wild type (WT) mice sensitized in the same manner; in contrast, only eosinophilic infiltration was not developed in IL-4-/- mice sensitized with OVA+alum compared to WT mice sensitized in the same manner (Table 1 and Figure 1B)
The levels of TGF-β1 in the BAL fluids were significantly lower in both the IL-4-/- and IL-13-/- mice that were sensitized with OVA+alum than in the WT mice sensitized in the same manner

Summary

Introduction

Asthma is an increasingly common disease that is characterized by airway hyperresponsiveness (AHR) and chronic inflammation and remodeling (Pueringer and Hunninghake, 1992). AHR, which is an exaggerated bronchoconstrictive response to non-specific agonists (e.g., methacholine), is considered the hallmark physiologic abnormality underlying asthmatic diathesis (Pueringer and Hunninghake, 1992; Weinberger, 1993; Whyte et al, 1993). Much evidence suggests that allergen-specific CD4+ Th2 cells play essential roles in initiating and generating this abnormality (Robinson et al, 1992; Robinson et al, 1993; Cohn et al, 1997). IL-4 and IL-5 cannot completely account for this physiologic response. In terms of the roles of Th2 cytokines in the

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Conclusion