IL-1 Receptor Accessory Protein and ST2 Comprise the IL-33 Receptor Complex
Discovery Research, Schering-Plough Biopharma (formerly DNAX Research), Palo Alto, CA 94304, USA.The Journal of Immunology (Impact Factor: 4.92). 09/2007; 179(4):2551-5. DOI: 10.4049/jimmunol.179.4.2551
IL-33 (IL-1F11) is a recently described member of the IL-1 family of cytokines that stimulates the generation of cells, cytokines, and Igs characteristic of a type 2 immune response. IL-33 mediates signal transduction through ST2, a receptor expressed on Th2 and mast cells. In this study, we demonstrate that IL-33 and ST2 form a complex with IL-1R accessory protein (IL-1RAcP), a signaling receptor subunit that is also a member of the IL-1R complex. Additionally, IL-1RAcP is required for IL-33-induced in vivo effects, and IL-33-mediated signal transduction can be inhibited by dominant-negative IL-1RAcP. The implications of this shared usage of IL-1RAcP by IL-1(alpha and beta) and IL-33 are discussed.
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- "IL-33 is released into the extracellular milieu after cellular damage, mechanical injury, or necrosis . The effects of IL-33 are mediated through its interaction with a heterodimeric receptor consisting of membrane-bound ST2 (also known as IL1RL1) and IL-1RAcP, leading to NF-jB and MAPK activation [1,456. IL-33 activates T cells [1,7], basophils , mast cells , eosinophils , innate lymphoid cells type 2 (ILC2) [11,12] and dendritic cells (DC)  , causing the production of proinflammatory mediators such as TNFa, IL-1b, IL-6 and IFN-c . "
ABSTRACT: Interleukin (IL)-33 is a member of the IL-1 family. IL-33 effects are mediated through its receptor, ST2 and IL-1RAcP, and its signaling induces the production of a number of pro-inflammatory mediators, including TNFα, IL-1β, IL-6, and IFN-γ. There are conflicting reports on the role of IL-33 in bone homeostasis, with some demonstrating a bone protective role for IL-33 whilst others show that IL-33 induces inflammatory arthritis with concurrent bone destruction. To better clarify the role IL-33 plays in bone biology in vivo, we studied IL-33 KO mice as well as mice in which the cytokine form of IL-33 was overexpressed. Mid-femur cortical bone mineral density (BMD) and bone strength were similar in the IL-33 KO mice compared to WT animals during the first 8 months of life. However, in the absence of IL-33, we observed higher BMD in lumbar vertebrae and distal femur in female mice. In contrast, overexpression of IL-33 resulted in a marked and rapid reduction of bone volume, mineral density and strength. Moreover, this was associated with a robust increase in inflammatory cytokines (including IL-6 and IFN-γ), suggesting the bone pathology could be a direct effect of IL-33 or an indirect effect due to the induction of other mediators. Furthermore, the detrimental bone effects were accompanied by increases in osteoclast number and the bone resorption marker of C-terminal telopeptide collagen-I (CTX-I). Together, these results demonstrate that absence of IL-33 has no negative consequences in normal bone homeostasis while high levels of circulating IL-33 contributes to pathological bone loss.
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- "IL-33 is only produced by innate immune cells including epithelial cells, DCs and macrophages (Schmitz et al., 2005; Rank et al., 2009; Pichery et al., 2012), and is released most probably when cells sense inflammatory signals or undergo necrosis (Moussion et al., 2008; Cayrol and Girard, 2009). IL-33 signals via its receptor ST2 and co-receptor IL-1R accessory protein (IL-1RAcP) (Schmitz et al., 2005; Ali et al., 2007; Chackerian et al., 2007). ST2 is expressed on a wide-range of innate immune cells (Schmitz et al., 2005; "
ABSTRACT: The pro-Th2 cytokine IL-33 is now emerging as an important Th1 cytokine-IFN-γ inducer in murine CD4+ T cells that is essential for protective cell-mediated immunity against viral infection in mice. However, whether IL-33 can promote human Th1 cell differentiation and how IL-33 polarizes Th1 cells is less understood. We assessed the ability of IL-33 to induce Th1 cell differentiation and IFN-γ production in vitro and in vivo. We report here that IL-33 alone had no ability in Th1 cell polarization. However it potentiated IL-12-mediated Th1 cell differentiation and IFN-γ production in TCR-stimulated murine and human CD4+ T cells in vitro and in vivo. IL-33 promoted Th1 cell development via MyD88 and synergized with IL-12 to enhance St2 and IL-12R expression in CD4+ T cells.
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- "Data show representative results from the two independent experiments performed, each of which gave similar results. Immunity 43, 175–186, July 21, 2015 ª2015 Elsevier Inc. 181 DISCUSSION It is now well established that IL-33 can induce Th2 cell-type inflammation accompanied by eosinophils, i.e., IL-33 can have pro-inflammatory effects (Chackerian et al., 2007; Kondo et al., 2008; Kurowska-Stolarska et al., 2008; Schmitz et al., 2005; Xu et al., 2008). Although IL-33 also can attenuate cardiomyocyte hypertrophy and cardiac fibrosis after pressure overload (Sanada et al., 2007), the molecular mechanisms accounting for these effects of IL-33 are not fully understood. "
ABSTRACT: House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells. Copyright © 2015 Elsevier Inc. All rights reserved.