Differential regulation of human and mouse IL33 expression in the lungs of human IL33 BAC transgenic mice.

Abstract

Abstract Interleukin-33 (IL33) is a member of the IL-1 cytokine family. IL33 polymorphisms are strongly associated with asthma susceptibility and IL33 deletion attenuates asthma in mice. However, the use of mouse models to elucidate the role of IL-33 in asthma is hampered by notably different tissue-specific patterns of IL33 expression in humans and mice. To bypass this limitation, we generated mice carrying a 157 kB human BAC transgene (TG) that includes IL33 and its flanking sequences on chromosome 9. This TG contains protective alleles for a number of asthma-associated polymorphisms. Five founders with 1, 2, or 6 BAC copies were obtained. All were healthy, fertile, and transmitted the transgene at the expected Mendelian ratio. To compare expression of transgenic human (h) and endogenous mouse (m)IL33, mice were challenged intranasally with Alternaria, which induces rapid release of mIL-33 in the lungs. Bronchoalveolar lavage fluid analysis showed that hIL-33 was also induced by Alternaria. Analysis of lung RNA by real-time PCR showed that Alternaria-induced hIL33 transcription was TG copy number-dependent and comparable with that of mIL33. IL33 is known to be expressed by human but not mouse endothelial cells. Indeed, we found high levels of hIL33 RNA in endothelial cell-enriched mouse CD31+ lung cells while mIL33 was barely detectable. These results suggest that tissue-specific hIL33 expression is controlled by cis-acting element(s) within the IL33 locus. More generally, our BAC TG appears to include all cis-regulatory elements necessary for faithful tissue-specific and copy number-dependent regulation of hIL33 expression, suggesting our mice are an ideal tool to study IL33 and its role in asthma.