Deletion of the ST2 proximal promoter disrupts fibroblast-specific expression but does not reduce the amount of soluble ST2 in circulation

Authors

  • Brian P. Lipsky,

    Corresponding author
    • Department of Inflammation Research, Amgen, Seattle, Washington
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  • Dean Y. Toy,

  • David A. Swart,

  • Molly D. Smithgall,

  • DirkE. Smith


Full Correspondence Dirk E. Smith, Amgen, 1201 Amgen Ct West, Seattle, WA 98119, USA

Fax: +1-206-265-7284

e-mail: smithde@amgen.com

Abstract

IL-33 signals through ST2, 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 ST2 mRNA 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 ST2 proximal promoter is deleted. Promoter deletion had no impact on ST2 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 ST2 mRNA in fibroblasts, which corresponded with both an inability to secrete soluble ST2 and a defect in IL-33 responsiveness. Importantly, in spite of the fibroblast defect, soluble ST2 concentrations were not reduced in the serum of naïve or allergen-exposed knockout mice. In summary, we found that ST2 promoter usage is largely cell-type dependent but does not dictate splicing. Moreover, the proximal promoter is not a major driver of circulating soluble ST2 under the conditions tested.

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