Deletion of the ST 2 proximal promoter disrupts fibroblast‐specific expression but does not reduce the amount of soluble ST 2 in circulation

• Published in: European journal of immunology 2012-07, Vol.42 (7), p.1863-1869
• Main Authors: Lipsky, Brian P., Toy, Dean Y., Swart, David A., Smithgall, Molly D., Smith, DirkE
• Format: Article
• Language: English
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201142274

IL ‐33 signals through ST 2, which is expressed either as a full‐length signaling receptor or a truncated soluble receptor that can suppress IL ‐33 activity. Previous data suggest that soluble ST 2 m RNA in fibroblasts is coupled to a serum‐inducible proximal promoter, while full‐length ST2 expression in immune cells is directed from a distal promoter. In order to better understand the function of the alternative promoters and how they ultimately affect the regulation of IL ‐33, we generated a mouse in which the ST 2 proximal promoter is deleted. Promoter deletion had no impact on ST 2 expression in mast cells or their ability to respond to IL ‐33. In contrast, it resulted in a complete loss of both soluble and full‐length ST 2 m RNA in fibroblasts, which corresponded with both an inability to secrete soluble ST 2 and a defect in IL ‐33 responsiveness. Importantly, in spite of the fibroblast defect, soluble ST 2 concentrations were not reduced in the serum of naïve or allergen‐exposed knockout mice. In summary, we found that ST 2 promoter usage is largely cell‐type dependent but does not dictate splicing. Moreover, the proximal promoter is not a major driver of circulating soluble ST 2 under the conditions tested.