Dissociation of T helper type 2 cytokine-dependent airway lesions from signal transducer and activator of transcription 6 signalling in experimental chronic asthma
Article first published online: 8 MAY 2003
Clinical & Experimental Allergy
Volume 33, Issue 5, pages 688–695, May 2003
How to Cite
Foster, P. S., Webb, D. C., Yang, M., Herbert, C. and Kumar, R. K. (2003), Dissociation of T helper type 2 cytokine-dependent airway lesions from signal transducer and activator of transcription 6 signalling in experimental chronic asthma. Clinical & Experimental Allergy, 33: 688–695. doi: 10.1046/j.1365-2222.2003.01647.x
- Issue published online: 8 MAY 2003
- Article first published online: 8 MAY 2003
- Submitted 12 September 2002; revised 13 January 2003; accepted 24 January 2003
- in vivo animal models;
Background Type 2 T helper lymphocytes (Th2 cells) and their cytokine products are important in the pathogenesis of asthma.
Objective To examine the contribution of the signal transducer and activator of transcription (STAT) 6 pathway, involved in Th2 cytokine signalling, to the development of lesions of chronic asthma.
Methods BALB/c mice sensitized to ovalbumin were chronically challenged by inhalational of low mass concentrations of antigen for 6 weeks. Airway lesions in wild-type mice were compared with those in STAT6-deficient mice and in IL-4/13 double-deficient mice by histomorphometry and immunohistochemistry. Airway responses to methacholine were evaluated by whole-body plethysmography. Cytokine production by peribronchial lymph node cells was quantified by enzyme immunoassay.
Results STAT6–/– mice developed a variety of airway lesions that were at least equivalent to those in wild-type mice, including accumulation of intraepithelial eosinophils and of chronic inflammatory cells in the lamina propria, subepithelial fibrosis and epithelial thickening. In addition, STAT6–/– mice exhibited exaggerated airway hyper-reactivity (AHR) compared to wild-type animals. This was despite a shift from a Th2 to a Th1 pattern of immunoglobulin production by plasma cells in the inflammatory infiltrate and diminished mucous cell hyperplasia/metaplasia, together with increased production of IFN-γ by peribronchial lymph node cells, consistent with absence of signalling via the STAT6 pathway. In contrast, gene-targeted IL-4/13–/– mice exhibited markedly diminished eosinophil recruitment and airway remodelling, as well as absence of AHR.
Conclusions In this model, the effects of STAT6 deficiency were in marked contrast to the suppression of inflammation and AHR described in models of allergic bronchopulmonary inflammation. These results, which provide evidence of STAT6-independent AHR in an inhalational challenge model of chronic asthma, emphasize the critical effector roles of IL-4 and IL-13, as well as the need to use appropriate models to understand cytokine signalling pathways that may be potential therapeutic targets in asthma.