Carriere V, Roussel L, Ortega N et al.IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci USA 104:282-287

Laboratoire de Biologie Vasculaire, Equipe Labellisée "La Ligue 2006," Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5089, 205 Route de Narbonne, 31077 Toulouse, France.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2007; 104(1):282-7. DOI: 10.1073/pnas.0606854104
Source: PubMed


Recent studies indicate that IL-1alpha functions intracellularly in pathways independent of its cell surface receptors by translocating to the nucleus and regulating transcription. Similarly, the chromatin-associated protein HMGB1 acts as both a nuclear factor and a secreted proinflammatory cytokine. Here, we show that IL-33, an IL-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines, is an endothelium-derived, chromatin-associated nuclear factor with transcriptional repressor properties. We found that IL-33 is identical to NF-HEV, a nuclear factor preferentially expressed in high endothelial venules (HEV), that we previously characterized. Accordingly, in situ hybridization demonstrated that endothelial cells constitute a major source of IL-33 mRNA in chronically inflamed tissues from patients with rheumatoid arthritis and Crohn's disease. Immunostaining with three distinct antisera, directed against the N-terminal part and IL-1-like C-terminal domain, revealed that IL-33 is a heterochromatin-associated nuclear factor in HEV endothelial cells in vivo. Association of IL-33 with heterochromatin was also observed in human and mouse cells under living conditions. In addition, colocalization of IL-33 with mitotic chromatin was noted. Nuclear localization, heterochromatin-association, and targeting to mitotic chromosomes were all found to be mediated by an evolutionarily conserved homeodomain-like helix-turn-helix motif within the IL-33 N-terminal part. Finally, IL-33 was found to possess transcriptional repressor properties, associated with the homeodomain-like helix-turn-helix motif. Together, these data suggest that, similarly to IL1alpha and HMGB1, IL-33 is a dual function protein that may function as both a proinflammatory cytokine and an intracellular nuclear factor with transcriptional regulatory properties.

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Available from: Gerard Bouche, Mar 10, 2015
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    • "IL-33 was identified in 2003 as a nuclear protein highly expressed in high endothelial venules (HEV) and initially named nuclear factor from HEV (NF-HEV) [2]. Full-length human IL-33 protein has 270 amino acids and contains a homeodomain-like helix-turn-helix in its N-terminus, important for nuclear localization, heterochromatin association and transcriptional repressor activities [2] [11]. On the other hand, full-length IL-33 can, through its N-terminal domain (amino acids 66–109), can interact with nuclear factor kB (NF-kB) transcription factor [12] (Fig. 1A). "
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    ABSTRACT: IL-33, an IL-1 family member, is expressed by many cell types and can regulate gene transcription. IL-33 is released upon cell necrosis and the precursor form is enzymatically processed, and then drives inflammation as a damage-associated molecular pattern. The IL-33 receptor ST2, encoded by IL1RL1, is expressed as both a membrane-anchored receptor (ST2L) activated by IL-33, and as a soluble variant (sST2) that exhibits anti-inflammatory properties. The IL-33/ST2 axis is involved in the pathogenesis of atopic and autoimmune diseases, cancer, and central nervous system disorders. Here, we review recent findings on the role of the IL-33/ST2 axis in health and disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cytokine & growth factor reviews 07/2015; DOI:10.1016/j.cytogfr.2015.07.017 · 5.36 Impact Factor
    • "Chromatin association is mediated by an evolutionarily conserved homeodomain-like helix-turn-helix motif within the IL-33 N-terminal part (Carriere et al., 2007; Roussel et al., 2008). This domain also associates with the p65 NF-kB subunit, preventing its binding to DNA and dampening NF-kB-dependent gene expression (Ali et al., 2011). "
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    ABSTRACT: Members of the extended interleukin-1 (IL-1) cytokine family, such as IL-1, IL-18, IL-33, and IL-36, play a pivotal role in the initiation and amplification of immune responses. However, deregulated production and/or activation of these cytokines can lead to the development of multiple inflammatory disorders. IL-1 family members share a broadly similar domain organization and receptor signaling pathways. Another striking similarity between IL-1 family members is the requirement for proteolytic processing in order to unlock their full biological potential. Although much emphasis has been put on the role of caspase-1, another emerging theme is the involvement of neutrophil- and mast cell-derived proteases in IL-1 family cytokine processing. Elucidating the regulation of IL-1 family members by proteolytic processing is of great interest for understanding inflammation and immunity. Here, we review the identity of the proteases involved in the proteolytic processing of IL-1 family cytokines and the therapeutic implications in inflammatory disease. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 06/2015; 42(6):991-1004. DOI:10.1016/j.immuni.2015.06.003 · 21.56 Impact Factor
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    • "IL - 33 has been ascribed a dual function , acting as a cytokine upon release into the extracellular space where it can induce signal transduction in cells expressing the IL - 33 receptor ST2 / IL - 1RAcP , or as a nuclear factor . In the absence of proinflammatory stimuli , IL - 33 localizes to the nucleus by associating with chro - matin ( Carriere et al . , 2007 ) and histones H2A – H2B via a short chromatin - binding motif and is suggested a role as a transcrip - tional repressor ( Roussel et al . , 2008 ) . How IL - 33 is released into the extracellular space from this nuclear localization is enigmatic as IL - 33 lacks a specific signal peptide to enable it to be processed for secretion via t"
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    ABSTRACT: Thymic Stromal Lymphopoietin (TSLP) and Interleukin 33 (IL-33) are two cytokines released by cells that are in proximity with our environment, e.g., keratinocytes of the skin and epithelial cells of the airways. Pathogens, allergens, chemicals and other agents induce the release of TSLP and IL-33, which are recognized by mast cells. TSLP and IL-33 affect several mast cell functions, including growth, survival and mediator release. These molecules do not directly induce exocytosis, but cause release of de novo synthesized lipid mediators and cytokines. TSLP and IL-33 are also implicated in inflammatory diseases where mast cells are known to be an important part of the pathogenesis, e.g., asthma and atopic dermatitis. In this chapter we describe and discuss the implications of TSLP and IL-33 on mast cell functions in health and disease. Copyright © 2015 Elsevier B.V. All rights reserved.
    European journal of pharmacology 06/2015; DOI:10.1016/j.ejphar.2015.04.047 · 2.53 Impact Factor
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