Transcript Signatures in Experimental Asthma: Identification of STAT6-Dependent and -Independent Pathways

Abstract

The analysis of polygenic diseases such as asthma poses a challenging problem. In an effort to provide unbiased insight into disease pathogenesis, we took an empirical approach involving transcript expression profiling of lung tissue from mice with experimental asthma. Asthmatic responses were found to involve sequential induction of 4.7% of the tested genome; notably, there was ectopic expression of a series of genes not previously implicated in allergic or pulmonary responses. Genes were widely distributed throughout all chromosomes, but preferentially included genes involved in immunity, development, and homeostasis. When asthma was induced by two independent experimental regimens, unique gene transcript profiles were found depending upon the mode of disease induction. However, the majority of genes were common to both models representing an asthma signature genome. Analysis of STAT6-deficient mice revealed that an unexpectedly large segment of the asthma genes were STAT6 independent; this correlated with sustained inflammatory events in these mice. Notably, induction of asthma in STAT6-deficient mice resulted in gene induction not seen in wild-type mice. These results raise concern that therapeutic blockade of STAT6 in the asthmatic setting may reprogram the genetic signature, resulting in alternative lung pathology, which we indeed observed in STAT6-deficient mice. These results provide unprecedented insight into the complex steps involved in the pathogenesis of allergic airway responses; as such, these results have significant therapeutic and clinical implications.

Gene expression analysis in a murine model of allergic asthma reveals overlapping disease and therapy dependent pathways in the lung

“…Consistent with the results of Zimmermann and coworkers, 18,22 we showed that two members of the trefoil family, P-domain protein (TFF1/pS2) and spasmolytic protein (TFF2/mSP), were induced by OVA challenge. We now show that trefoil expression was completely dependent on IL-13 signaling.…”

Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation

“…To address the mechanism whereby IL-13 is differentially expressed in the airways of these mice and to understand the relationship of AMCase expression to other regulatory factors important in airway differentiation, we analyzed Foxa2 expression in the ovalbumin-challenged and IL-13 transgenic mice. It has previously been shown that STAT-6 signaling and IL-13 are required for AMCase expression (60). Thus IL-13 signaling is clearly taking place in the AMCase-producing distal cells.…”

“…Furthermore, the production of AMCase, Ym1, and mucus in response to IL-13 is STAT6 dependent (27,53,60). Difference in an IL-13-induced phenotype despite similar signaling pathways has previously been shown in cells of different lineages as well as in airway cells under different culture conditions (25,29).…”

“…Both Ym1 and Ym2 proteins, related members of the chitinase family, are dramatically upregulated in the presence of Th2 inflammation (43,52,60). To determine whether the staining pattern for AMCase is typical of all members of the chitinase family, we performed in situ hybridization for Ym1 in ovalbumin-challenged and IL-13 transgenic mice ( Figs.…”

“…Paradoxically, although chitin and chitin synthase do not exist in mammals, human chitinase family members such as acidic mammalian chitinase (AMCase) have recently been described (5). Our laboratory and others have previously shown that AMCase and Ym1 are specifically upregulated in response to Th2 inflammation in the lung (43,59,60). Furthermore, inhibition of AMCase by a variety of means inhibits this inflammation (59).…”