[Show abstract][Hide abstract] 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.
Preview · Article · Jul 2012 · European Journal of Immunology
[Show abstract][Hide abstract] ABSTRACT: IL-33 is an IL-1 family member recently identified as the ligand for T1/ST2 (ST2), a member of the IL-1 receptor family. ST2
is stably expressed on mast cells and Th2 effector T cells and its function has been studied in the context of Th2-associated inflammation. Indeed, IL-33 induces Th2 cytokines from mast cells and polarized mouse T cells and leads to pulmonary and mucosal Th2 inflammation when administered in vivo. To better understand how this pathway modulates inflammatory responses, we examined the activity of IL-33 on a variety of
human immune cells. Human blood-derived basophils expressed high levels of ST2 receptor and responded to IL-33 by producing
several pro-inflammatory cytokines including IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13 and granulocyte macrophage colony-stimulating
factor. Next, utilizing a human Th2-polarized T cell culture system derived from allergic donor blood cells, we found that IL-33 was able to enhance antigen-dependent
and -independent T cell responses, including IL-5, IL-13 and IFN-γ production. IL-33 activity was also tested on Vα24-positive
human invariant NKT (iNKT) cells. In the presence of α-galactosylceramide antigen presentation, IL-33 dose dependently enhanced
iNKT production of several cytokines, including both IL-4 and IFN-γ. IL-33 also directly induced IFN-γ production from both
iNKT and human NK cells via cooperation with IL-12. Taken together, these results indicate that in addition to its activity
on human mast cells, IL-33 is capable of activating human basophils, polarized T cells, iNKT and NK cells. Moreover, the nature
of the responses elicited by IL-33 suggests that this axis may amplify both Th1- and Th2-oriented immune responses.
Preview · Article · Jul 2008 · International Immunology
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-33 (or IL-1F11) was recently identified as a ligand for the orphan IL-1 receptor family member T1/ST2 (ST2). IL-33 belongs to the IL-1 cytokine family and, upon binding to ST2, induces intracellular signals similar to those utilized by IL-1. The effects of other IL-1 family cytokines are mediated by their binding to a specific receptor and the recruitment of a co-receptor required for elicitation of signaling. The aim of this study was to characterize the co-receptor involved in IL-33 signaling. Immunoprecipitation confirmed that IL-33 specifically binds ST2 and revealed that cellular IL-1 receptor accessory protein (AcP) associates with ST2 in a ligand-dependent manner. Receptor binding measurements demonstrated that the affinity of mouse (m)IL-33 for ST2 is increased by 4-fold in presence of AcP. IL-33 dose-dependently stimulated IL-6 secretion from wild-type (WT) mast cells, while no effect of IL-33 was observed with mast cells derived from AcP-deficient mice. Finally, soluble (s)ST2-Fc and sAcP-Fc acted synergistically to inhibit IL-33 activity. These observations identify AcP as a shared co-receptor within the IL-1 family that is essential for IL-33 signaling and suggest a novel role for sAcP in modulating the activity of IL-33.