The 3′ untranslated region of the membrane-bound IL-IR accessory protein mRNA confers tissue-specific destabilization

IL-1alpha and IL-1beta are proinflammatory cytokines that promote activation of intracellular signaling cascades, leading to stabilization of certain mRNAs and activation of transcription factors. 1L-1R type I (IL-1RI) binds IL-1alpha and IL-1beta, and subsequent recruitment of the membrane-bound IL-1R accessory protein (m1L-1RAcP) facilitates signal transduction. Two alternatively spliced isoforms, soluble 1L-lRAcP (s1L-1RAcP) and sIL-1RAcP-beta, which lack transmembrane and intracellular domains, have been described. The s1L-1RAcP and possibly- sIL-IRAcP-beta can inhibit IL-1 signaling, Proportional expression of the different 1L-1RAcP splice variants may be an important determinant of responsiveness to IL-1. We show that although both m1L-1RAcP and s1L-1RAcP mRNAs are widely expressed in human tissue, their relative proportions differ significantly in a tissue-specific manner. Turnover studies revealed that the s1L-1RAcP mRNA has a half-life of similar to48 h in both the kidney cell line 293 and the hepatoma cell line HepG2. The m1L-1RAcP mRNA has a similar half-life in 293 cells, but a considerably shorter half-life of similar to5 h in HepG2 cells. Using luciferase reporter constructs, we demonstrated that this specific destabilization of the m1L-1RAcP mRNA in the latter cell type is mediated by its 2.8-kb 3'-untranslated region. Deletion analysis further established that the cell line-specific instability does not involve AU-rich elements, but is mediated by several novel elements that appear to act independently; such elements may be recognized by proteins expressed specifically in some, but not all, tissues. These data demonstrate that the cellular capacity to respond to IL-1 is tightly regulated in a tissue-specific manner.