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
Source: PubMed


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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    • "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. "
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    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.
    Immunity 07/2015; 43(1):175-86. DOI:10.1016/j.immuni.2015.06.021 · 21.56 Impact Factor
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    • "IL-33 is a ligand for a receptor complex consisting of two proteins: IL-1 receptorrelated protein (IL-1RL1, ST2) and IL-1 receptor accessory protein (IL-1RAcP). IL-1RAcP is required for IL-33-induced signal transduction and in vivo effects, but is unable to directly bind to IL-33 or ST2 by itself [1]. Structurally, IL-33 binds to ST2 and forms suitable conformations to contact with IL-1RAcP [2]. "
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    ABSTRACT: Interleukin (IL)-33 signals influence various immune cells during differentiation, immune responses and homeostasis. As discussed in this Review, IL-33 via TI/ST2L regulates the functions of immune cells including T cells, B cells, DCs, macrophages, mast cells, and innate lymphoid cells (ILCs). Stimulation with IL-33 is crucial for CD4+ T cell polarized into Th2 immunity and for the induction of Treg. CD8+ T cells can also express ST2L and IL-33 promotes features of effector CD8+ T cells. For macrophages and ILCs, ST2L presents on these cells and IL-33 induces Th2 cytokine production. IL-33 modulates adhesion, activation, maturation, and cytokine production by mast cells. ST2 is expressed in B1 and is important for differentiation of IL-10-producing B cells. Understanding the specific role of IL-33/ST2L in different immune cells will help to answer the remaining questions that are important for diseases pathologies and intervention strategies by targeting the IL-33/ST2L signals.
    Immunology Letters 02/2015; 179(1). DOI:10.1016/j.imlet.2015.01.008 · 2.51 Impact Factor
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    • "It is described as a cytokine with two different functions: it acts as an intracellular regulator of gene expression (Carriere et al., 2007; Ali et al., 2011) and as an alarm mediator when released from damaged cells (Cayrol and Girard, 2009; Lamkanfi and Dixit, 2009; Lüthi et al., 2009). Nuclear IL-33 can interact with the transcription factor nuclear factor kappa-B (NF-jB) and dampen its activity in non–IL-33 receptor mediated fashion (Carriere et al., 2007; Ali et al., 2011), whereas extracellular IL-33 binds to its receptor consisting of a heterodimer between ST2 and IL-1 receptor accessory protein (IL-1RAcP) (Ali et al., 2007; Chackerian et al., 2007; Liew et al., 2010; Liu et al., 2013). The IL-33 receptor is expressed on a broad range of immune cells, including Th2 cells and macrophages, and can promote Th2 cell expansion and shift the macrophage polarization from M1 to M2 (Xu et al., 1998; Schmitz et al., 2005; Kurowska-Stolarska et al., 2009; Miller et al., 2010). "
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    ABSTRACT: Interleukin-33 (IL-33) is a member of the interleukin-1 cytokine family and highly expressed in the naïve mouse brain and spinal cord. Despite the fact that IL-33 is known to be inducible by various inflammatory stimuli, its cellular localization in the central nervous system and role in pathological conditions is controversial. Administration of recombinant IL-33 has been shown to attenuate experimental autoimmune encephalomyelitis progression in one study, yet contradictory reports also exist. Here we investigated for the first time the pattern of IL-33 expression in the contused mouse spinal cord and demonstrated that after spinal cord injury (SCI) IL-33 was up-regulated and exhibited a nuclear localization predominantly in astrocytes. Importantly, we found that treatment with recombinant IL-33 alleviated secondary damage by significantly decreasing tissue loss, demyelination and astrogliosis in the contused mouse spinal cord, resulting in dramatically improved functional recovery. We identified both central and peripheral mechanisms of IL-33 action. In spinal cord, IL-33 treatment reduced the expression of pro-inflammatory tumor necrosis factor-alpha and promoted the activation of anti-inflammatory arginase-1 positive M2 microglia/macrophages, which chronically persisted in the injured spinal cord for up to at least 42days after the treatment. In addition, IL-33 treatment showed a tendency towards reduced T-cell infiltration into the spinal cord. In the periphery, IL-33 treatment induced a shift towards the Th2 type cytokine profile and reduced the percentage and absolute number of cytotoxic, tumor necrosis factor-alpha expressing CD4+ cells in the spleen. Additionally, IL-33 treatment increased expression of T-regulatory cell marker FoxP3 and reduced expression of M1 marker iNOS in the spleen. Taken together, these results provide the first evidence that IL-33 administration is beneficial after CNS trauma. Treatment with IL33 may offer a novel therapeutic strategy for patients with acute contusion SCI.
    Brain Behavior and Immunity 08/2014; · 5.89 Impact Factor
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