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Penelope Pelczar, Mario Witkowski, Laura Garcia Perez, Jan Kempski, Anna G Hammel, Leonie Brockmann, Dörte Kleinschmidt, Sandra Wende, Cathleen Haueis, Tanja Bedke, Marco Witkowski, Susanne Krasemann, Stefan Steurer, Carmen J Booth, Philipp Busch, Alexandra König, Ursula Rauch, Daniel Benten, Jakob R Izbicki, Thomas Rösch, Ansgar W Lohse, Till Strowig, Nicola Gagliani, Richard A Flavell, Samuel Huber
Intestinal inflammation can impair mucosal healing, thereby establishing a vicious cycle leading to chronic inflammatory bowel disease (IBD). However, the signaling networks driving chronic inflammation remain unclear. Here we report that CD4(+) T cells isolated from patients with IBD produce high levels of interleukin-22 binding protein (IL-22BP), the endogenous inhibitor of the tissue-protective cytokine IL-22. Using mouse models, we demonstrate that IBD development requires T cell-derived IL-22BP. Lastly, intestinal CD4(+) T cells isolated from IBD patients responsive to treatment with antibodies against tumor necrosis factor-α (anti-TNF-α), the most effective known IBD therapy, exhibited reduced amounts of IL-22BP expression but still expressed IL-22...
October 21, 2016: Science
Chrissie Lim, MeeAe Hong, Ram Savan
The cytokine interleukin-22 (IL-22), which is a member of the IL-10 family, is produced exclusively by immune cells and activates signal transducer and activator of transcription 3 (STAT3) in nonimmune cells, such as hepatocytes, keratinocytes, and colonic epithelial cells, to drive various processes central to tissue homeostasis and immunosurveillance. Dysregulation of IL-22 signaling causes inflammatory diseases. IL-22 binding protein (IL-22BP; encoded by IL22RA2) is a soluble IL-22 receptor, which antagonizes IL-22 activity and has genetic associations with autoimmune diseases...
2016: Science Signaling
Rojo A Ratsimandresy, Mohanalaxmi Indramohan, Andrea Dorfleutner, Christian Stehlik
Inflammasomes are important for maintaining intestinal homeostasis, and dysbiosis contributes to the pathology of inflammatory bowel disease (IBD) and increases the risk for colorectal cancer. Inflammasome defects contribute to chronic intestinal inflammation and increase the susceptibility to colitis in mice. However, the inflammasome sensor absent in melanoma 2 (AIM2) protects against colorectal cancer in an inflammasome-independent manner through DNA-dependent protein kinase and Akt pathways. Yet, the roles of the AIM2 inflammasome in IBD and the early phases of colorectal cancer remain ill-defined...
January 2017: Cellular & Molecular Immunology
Shi Bin Yang, Fanghai Han, Jian Hai Wu, Zhi Zhao, Wenhua Zhan
C-X-C motif chemokine receptor type 2 (CXCR2), a key regulatory protein, has been associated with multiple roles in the progression of numerous tumors, including gastric adenocarcinoma (GA). However, the mechanism of CXCR2 in the development of tumors remains controversial and unclear. In a previous study, the expression of CXCR2 and interleukin-22 receptor 2 (IL-22BP) was observed in GA. This promoted the present study, which aimed to explore the association between the two proteins, and to further analyze their roles in GA...
August 2016: Oncology Letters
Julia O Misiorek, Iris A K Lähdeniemi, Joel H Nyström, Valeriy M Paramonov, Josef A Gullmets, Helena Saarento, Adolfo Rivero-Müller, Trine Husøy, Pekka Taimen, Diana M Toivola
Keratins (K) are intermediate filament proteins important in protection from cellular stress. K8, K18 and K19 are the main components of keratin filaments in colonic epithelia but their role in intestinal diseases remains ambiguous. A function for keratins in intestinal health is supported by the K8-knock-out (K8(-/-)) mouse which manifests an early chronic ulcerative colitis-like inflammatory bowel disease and epithelial hyperproliferation. We tested whether K8(-/-) mice are more susceptible to colorectal cancer (CRC) compared to K8 wild type (K8(+/+)), and K8 heterozygote (K8(+/-)) mice showing increased proliferation but no inflammation...
August 2016: Carcinogenesis
J C Martin, G Bériou, M Heslan, C Bossard, A Jarry, A Abidi, P Hulin, S Ménoret, R Thinard, I Anegon, C Jacqueline, B Lardeux, F Halary, J-C Renauld, A Bourreille, R Josien
Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel diseases (IBDs), are characterized by high levels of IL-22 production. Rodent studies revealed that this cytokine is protective during colitis but whether this is true in IBDs is unclear. We show here that levels of the soluble inhibitor of IL-22, interleukin 22-binding protein (IL-22BP), are significantly enhanced during IBDs owing to increased numbers of IL-22BP-producing eosinophils, that we unexpectedly identify as the most abundant source of IL-22BP protein in human gut...
March 2016: Mucosal Immunology
Guillaume Perriard, Amandine Mathias, Lukas Enz, Mathieu Canales, Myriam Schluep, Melanie Gentner, Nicole Schaeren-Wiemers, Renaud A Du Pasquier
BACKGROUND: Increasing evidences link T helper 17 (Th17) cells with multiple sclerosis (MS). In this context, interleukin-22 (IL-22), a Th17-linked cytokine, has been implicated in blood brain barrier breakdown and lymphocyte infiltration. Furthermore, polymorphism between MS patients and controls has been recently described in the gene coding for IL-22 binding protein (IL-22BP). Here, we aimed to better characterize IL-22 in the context of MS. METHODS: IL-22 and IL-22BP expressions were assessed by ELISA and qPCR in the following compartments of MS patients and control subjects: (1) the serum, (2) the cerebrospinal fluid, and (3) immune cells of peripheral blood...
2015: Journal of Neuroinflammation
F Ciccia, G Guggino, A Rizzo, M Bombardieri, S Raimondo, F Carubbi, A Cannizzaro, G Sireci, F Dieli, G Campisi, R Giacomelli, Paola Cipriani, G De Leo, R Alessandro, G Triolo
The aim of this study was to elucidate more clearly the role of interleukin (IL)-18 in modulating the IL-22 pathway in primary Sjögren's syndrome (pSS) patients and in pSS-associated lymphomas. Minor salivary glands (MSGs) from patients with pSS and non-specific chronic sialoadenitis (nSCS), parotid glands biopsies from non-Hodgkin lymphomas (NHL) developed in pSS patients, were evaluated for IL-18, IL-22, IL-22 receptor 1 (IL-22R1), IL-22 binding protein (IL-22BP) and signal transducer and activator of transcription-3 (STAT-3) expression...
August 2015: Clinical and Experimental Immunology
Mathieu Sertorio, Xunya Hou, Rodrigo F Carmo, Hélia Dessein, Sandrine Cabantous, Mohammed Abdelwahed, Audrey Romano, Fernanda Albuquerque, Luydson Vasconcelos, Theomira Carmo, Jun Li, Arthur Varoquaux, Violaine Arnaud, Pablo Oliveira, Anas Hamdoun, Hongbin He, Suzan Adbelmaboud, Adil Mergani, Jie Zhou, Ahmed Monis, Leila Beltrao Pereira, Philippe Halfon, Marc Bourlière, Raymundo Parana, Mitermayer Dos Reis, David Gonnelli, Patricia Moura, Nasr Eldin Elwali, Laurent Argiro, Yuesheng Li, Alain Dessein
UNLABELLED: Interleukin (IL)-22 acts on epithelia, hepatocytes, and pancreatic cells and stimulates innate immunity, tissue protection, and repair. IL-22 may also cause inflammation and abnormal cell proliferation. The binding of IL-22 to its receptor is competed by IL-22 binding protein (IL-22BP), which may limit the deleterious effects of IL-22. The role of IL-22 and IL-22BP in chronic liver diseases is unknown. We addressed this question in individuals chronically infected with schistosomes or hepatitis C virus (HCV)...
April 2015: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Xuyan Yang, Yin Gao, Huiying Wang, Xiaoying Zhao, Xubo Gong, Qingqing Wang, Xiaofei Zhang
OBJECTIVE: Interleukin 22 (IL-22) plays an important role in the promotion of antimicrobial immunity. However, dysregulated IL-22 action leads to inflammation and is involved in autoimmune diseases, including systemic lupus erythematosus (SLE). IL-22 binding protein (IL-22BP) is a soluble inhibitory IL-22 receptor and may represent a crucial regulator of IL-22. We investigated the expression and potential significance of serum and urinary IL-22BP levels in patients with SLE. METHODS: A total of 112 patients with SLE and healthy control subjects participated in our study...
September 2014: Journal of Rheumatology
H Laaksonen, A O Guerreiro-Cacais, M Z Adzemovic, R Parsa, M Zeitelhofer, M Jagodic, T Olsson
Single-nucleotide polymorphisms close to IL22RA2, coding for the soluble interleukin (IL)-22-binding protein (IL-22BP), are strongly and reproducibly associated with multiple sclerosis (MS), but there is little data on how this molecule may affect neuroinflammation. Here, we have studied the mouse ortholog in C57BL/6 wild-type and Il22ra2-deficient mice in the context of experimental autoimmune encephalomyelitis (myelin oligodendrocyte glycoprotein-EAE). In wild-type mice, we demonstrated changes in the levels of transcripts for IL-22, the signaling IL-22 receptor and IL-22BP in lymphoid tissues at the time of T-cell priming and in the inflamed central nervous system (CNS)...
October 2014: Genes and Immunity
Francesco Ciccia, Aroldo Rizzo, Riccardo Alessandro, Giuliana Guggino, Rosario Maugeri, Laura Saieva, Alessandra Cannizzaro, AnnaRita Giardina, Giacomo De Leo, Domenico Gerardo Iacopino, Giovanni Triolo
OBJECTIVE: The aim of this study was to assess the expression of IL-22, IL-22 receptor 1 (IL-22R1), IL-22 binding protein (IL-22BP) and p-STAT3 in muscle tissue from patients with PM and DM. METHODS: Levels of IL-22, IL-22R1, IL-22BP and STAT3 mRNA were quantified by RT-PCR. The expression of IL-22, IL-22R1, IL-22BP and p-STAT3 was also analysed using immunohistochemistry. RESULTS: Significant modulation of the IL-22 pathway was observed in inflammatory myopathic tissues...
July 2014: Rheumatology
J C J Martin, G Bériou, M Heslan, C Chauvin, L Utriainen, A Aumeunier, C L Scott, A Mowat, V Cerovic, S A Houston, M Leboeuf, F X Hubert, C Hémont, M Merad, S Milling, R Josien
Interleukin-22 (IL-22) is mainly produced at barrier surfaces by T cells and innate lymphoid cells and is crucial to maintain epithelial integrity. However, dysregulated IL-22 action leads to deleterious inflammation and is involved in diseases such as psoriasis, intestinal inflammation, and cancer. IL-22 binding protein (IL-22BP) is a soluble inhibitory IL-22 receptor and may represent a crucial regulator of IL-22. We show both in rats and mice that, in the steady state, the main source of IL-22BP is constituted by a subset of conventional dendritic cells (DCs) in lymphoid and non-lymphoid tissues...
January 2014: Mucosal Immunology
Samuel Huber, Nicola Gagliani, Lauren A Zenewicz, Francis J Huber, Lidia Bosurgi, Bo Hu, Matija Hedl, Wei Zhang, William O'Connor, Andrew J Murphy, David M Valenzuela, George D Yancopoulos, Carmen J Booth, Judy H Cho, Wenjun Ouyang, Clara Abraham, Richard A Flavell
Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. Interleukin 22 (IL-22), a cytokine of the IL-10 superfamily, has an important role in colonic epithelial cell repair, and its levels are increased in the blood and intestine of inflammatory bowel disease patients...
November 8, 2012: Nature
Muriel M Lemaire, Aurélie Vanhaudenarde, Yannick Nizet, Laure Dumoutier, Jean-Christophe Renauld
Induction of autoantibodies towards immune regulatory proteins, such as cytokines or their receptors, is a powerful strategy for functional studies on the role of these factors in vivo. Here we describe a new procedure to elicit autoantibodies by taking advantage of tumor cells as a vaccine against peptides presented at their surface in fusion with the human CD134L transmembrane protein. P1.HTR, an immunogenic variant of the P815 mastocytoma cell line, was used to generate stably transfected cell clones with expression vectors encoding the human CD134L transmembrane protein fused with either mouse IL-22BP or IL-9...
March 31, 2011: Journal of Immunological Methods
Patricia Ribeiro de Moura, Leandra Watanabe, Lucas Bleicher, Didier Colau, Laure Dumoutier, Muriel M Lemaire, Jean-Christophe Renauld, Igor Polikarpov
Interleukin-22 (IL-22) plays an important role in the regulation of immune and inflammatory responses in mammals. The IL-22 binding protein (IL-22BP), a soluble receptor that specifically binds IL-22, prevents the IL-22/interleukin-22 receptor 1 (IL-22R1)/interleukin-10 receptor 2 (IL-10R2) complex assembly and blocks IL-22 biological activity. Here we present the crystal structure of the IL-22/IL-22BP complex at 2.75 A resolution. The structure reveals IL-22BP residues critical for IL-22 binding, which were confirmed by site-directed mutagenesis and functional studies...
April 2, 2009: FEBS Letters
Leandra Watanabe, Patricia Ribeiro de Moura, Alessandro Silva Nascimento, Didier Colau, Laure Dumoutier, Jean Christophe Renauld, Igor Polikarpov
Interleukin-22 (IL-22) is a pleiotropic cytokine that is involved in inflammatory responses. Human IL-22 was incubated with its soluble decoy receptor IL-22BP (IL-22 binding protein) and the IL-22-IL-22BP complex was crystallized in hanging drops using the vapour-diffusion method. Suitable crystals were obtained from polyethylene glycol solutions and diffraction data were collected to 2.75 A resolution. The crystal belonged to the tetragonal space group P4(1), with unit-cell parameters a = b = 67.9, c = 172...
February 1, 2009: Acta Crystallographica. Section F, Structural Biology and Crystallization Communications
Paul W Wu, Jing Li, Sreekumar R Kodangattil, Deborah P Luxenberg, Frann Bennett, Margot Martino, Mary Collins, Kyriaki Dunussi-Joannopoulos, Davinder S Gill, Neil M Wolfman, Lynette A Fouser
Interleukin (IL) 22 is a type II cytokine that is produced by immune cells and acts on nonimmune cells to regulate local tissue inflammation. As a product of the recently identified T helper 17 lineage of CD4(+) effector lymphocytes, IL-22 plays a critical role in mucosal immunity as well as in dysregulated inflammation observed in autoimmune diseases. We used comprehensive mutagenesis combined with mammalian cell expression, ELISA cell-based, and structural methods to evaluate how IL-22 interacts with its cell surface receptor, IL-22R/IL-10R2, and with secreted IL-22 binding protein...
October 24, 2008: Journal of Molecular Biology
Brandi C Jones, Naomi J Logsdon, Mark R Walter
IL-22 is an IL-10 family cytokine that initiates innate immune responses against bacterial pathogens and contributes to immune disease. IL-22 biological activity is initiated by binding to a cell-surface complex composed of IL-22R1 and IL-10R2 receptor chains and further regulated by interactions with a soluble binding protein, IL-22BP, which shares sequence similarity with an extracellular region of IL-22R1 (sIL-22R1). IL-22R1 also pairs with the IL-20R2 chain to induce IL-20 and IL-24 signaling. To define the molecular basis of these diverse interactions, we have determined the structure of the IL-22/sIL-22R1 complex...
September 10, 2008: Structure
Kerstin Wolk, Ellen Witte, Ute Hoffmann, Wolf-Dietrich Doecke, Stefanie Endesfelder, Khusru Asadullah, Wolfram Sterry, Hans-Dieter Volk, Bianca Maria Wittig, Robert Sabat
Crohn's disease (CD) is a common, chronic, inflammatory bowel disease characterized by intestinal infiltration of activated immune cells and distortion of the intestinal architecture. In this study, we demonstrate that IL-22, a cytokine that is mainly produced by activated Th1 and Th17 cells, was present in high quantities in the blood of CD patients in contrast to IFN-gamma and IL-17. In a mouse colitis model, IL-22 mRNA expression was elevated predominantly in the inflamed intestine but also in the mesenteric lymph nodes...
May 1, 2007: Journal of Immunology: Official Journal of the American Association of Immunologists
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