Bronchial hyperresponsiveness in experimental eosinophil-associated GI diseases is critically regulated by CD4 + T-cells, interleukin-13 and eotaxin

Abstract

Rationale Eosinophil-associated gastrointestinal diseases (EGID) are frequently associated with extraintestinal features including bronchopulmonary manifestations. The factors predisposing to bronchial hyperresponsiveness (BHR) in EGID are unknown. To elucidate the mechanistic link between EGID and BHR we employed murine models of EGID and eotaxin-1 (eotaxin)-transgene induced EGID. Methods Mice were sensitized and orally challenged with ovalbumin coated encapsulated particles to induce EGID and bronchial responsiveness was examined. Furthermore, transgenic mice expressing eotaxin in the intestine (using the rat fatty acid-binding promoter) were used to specifically elucidate the contribution of this chemokine in EGID-associated BHR. Results We show induction of allergen-induced EGID directly correlated with the development of BHR. The development of BHR in mice with allergen-induced EGID was dependent on eotaxin expression in the GI tract. Expression of eotaxin in the gastrointestinal tract of transgenic mice was sufficient to promote BHR. BHR was shown to be directly linked to the aberrant CD4 + Th 2-type T-cell (Th 2) production of interleukin-(IL)-13. Interestingly, transgenic expression of eotaxin was linked with enhanced Th 2-cytokine synthesis (IL-4, -5 and -13) and the production of mucosal IgG 1 in the gastrointestinal lumen. We also show that eotaxin treatment of CD4 + T-cells enhances IL-13 production in vitro. Conclusions These studies suggest that elevated expression of eotaxin in the gastrointestinal compartment can lead to increased CD4 + T-cell derived Th 2-cytokine production that drives aberrant immunophysiological responses in distant non-inflamed mucosal tissue (the lung). These results provide a possible explanation for altered lung function seen in some patients with inflammatory gastrointestinal disorders.