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The Intestinal Epithelium Accumulation of Reactive Oxygen Species in Maintains Intestinal Integrity by Preventing Activated Kina

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The Intestinal Epithelium Accumulation of Reactive Oxygen Species in Maintains Intestinal Integrity by Preventing Activated Kina TGF-β−Activated Kinase 1 Signaling Maintains Intestinal Integrity by Preventing Accumulation of Reactive Oxygen Species in the Intestinal Epithelium This information is current as of September 25, 2021. Rie Kajino-Sakamoto, Emily Omori, Prashant K. Nighot, Anthony T. Blikslager, Kunihiro Matsumoto and Jun Ninomiya-Tsuji J Immunol 2010; 185:4729-4737; Prepublished online 20 September 2010; Downloaded from doi: 10.4049/jimmunol.0903587 http://www.jimmunol.org/content/185/8/4729 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2010/09/17/jimmunol.090358 Material 7.DC1 References This article cites 41 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/185/8/4729.full#ref-list-1 Why The JI? Submit online. by guest on September 25, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology TGF-b–Activated Kinase 1 Signaling Maintains Intestinal Integrity by Preventing Accumulation of Reactive Oxygen Species in the Intestinal Epithelium Rie Kajino-Sakamoto,* Emily Omori,* Prashant K. Nighot,† Anthony T. Blikslager,† Kunihiro Matsumoto,‡ and Jun Ninomiya-Tsuji* The intestinal epithelium is constantly exposed to inducers of reactive oxygen species (ROS), such as commensal microorganisms. Levels of ROS are normally maintained at nontoxic levels, but dysregulation of ROS is involved in intestinal inflammatory diseases. In this article, we report that TGF-b–activated kinase 1 (TAK1) is a key regulator of ROS in the intestinal epithelium. tak1 gene deletion in the mouse intestinal epithelium caused tissue damage involving enterocyte apoptosis, disruption of tight junctions, and inflammation. Disruption of TNF signaling, which is a major intestinal damage inducer, rescued the inflammatory conditions but Downloaded from not apoptosis or disruption of tight junctions in the TAK1-deficient intestinal epithelium, suggesting that TNF is not a primary inducer of the damage noted in TAK1-deficient intestinal epithelium. We found that TAK1 deficiency resulted in reduced expres- sion of several antioxidant-responsive genes and reduced the protein level of a key antioxidant transcription factor NF-E2–related factor 2, which resulted in accumulation of ROS. Exogenous antioxidant treatment reduced apoptosis and disruption of tight junctions in the TAK1-deficient intestinal epithelium. Thus, TAK1 signaling regulates ROS through transcription factor NF-E2– related factor 2, which is important for intestinal epithelial integrity. The Journal of Immunology, 2010, 185: 4729–4737. http://www.jimmunol.org/ ntegrity of the epithelial barrier is essential for preventing role in intestinal epithelial barrier function (3, 4). For example, invasion of microorganisms and the development of chronic depletion of commensal bacteria greatly increases sensitivity to I inflammatory conditions in the intestine. A single layer of en- stress-induced intestinal damage (4). Ablation of TLR signaling terocytes separates the lamina propria from the gut lumen, there- from commensal bacteria disrupts the integrity of tight junctions by functioning as a physical barrier. Enterocytes are derived from in enterocytes (5). Therefore, commensal bacteria-derived cell intestinal epithelial stem cells that are localized to the crypts. Pro- signaling is likely to play a crucial role in cell survival and reg- liferating enterocytes differentiate and migrate toward the vil- ulation of tight junctions in enterocytes. However, the intracellular lus tips in the small intestine (1). Enterocytes undergo apoptosis signaling pathways that maintain enterocyte survival and tight by guest on September 25, 2021 only at the apical component of the villi. Although the intestine is junctions remain elusive. constantly exposed to high levels of cell-death inducers, such as TGF-b–activated kinase 1 (TAK1) plays an important role in TNF and bacteria-derived stressors, enterocytes are resistant to several innate immune-signaling pathways. TAK1 is activated by those inducers and survive until they reach the tip of the villus. TLR ligands, the intracellular bacteria sensor NOD2, and cyto- Dysregulated apoptosis during the periods of proliferation and kines (e.g., TNF and IL-1) (6–8). The TAK1-signaling pathway migration disrupts the intestinal barrier. In addition to enterocyte leads to activation of two groups of transcription factors, AP-1 survival, tightly connected enterocyte–enterocyte junctions (tight and NF-kB, which are intimately involved in immune responses junctions) are essential to form the physical barrier (2). Recently, in immune cells (9). We recently reported that TAK1 deficiency it has become evident that commensal bacteria play a protective results in dysregulation of cell survival in two types of epithelial cells: keratinocytes and enterocytes (10, 11). These findings raised the possibility that commensal bacteria-induced TAK1 signaling *Department of Environmental and Molecular Toxicology, North Carolina State Uni- versity, Raleigh, NC 27695; †Department of Clinical Sciences, College of Veterinary regulates enterocyte survival. Medicine, North Carolina State University, Raleigh, NC 27606; and ‡Department of TNF is constitutively expressed in the intestine and is essential Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, Japan for preventing the invasion of microorganisms (12). However, Received for publication November 5, 2009. Accepted for publication August 16, dysregulation in TNF signaling plays a major role in intestinal 2010. damage by inducing inflammation and apoptosis in inflammatory This work was supported by National Institutes of Health Grants RO1GM068812 and diseases, such Crohn’s disease, and inhibition of TNF signaling is RO1GM084406 and the Crohn’s and Colitis Foundation of America (to J.N.-T.). one of the most effective approaches to prevent intestinal damage Address correspondence and reprint requests to Dr. Jun Ninomiya-Tsuji, Department of Environmental and Molecular Toxicology, North Carolina State University, Cam- (13). TNF transcriptionally induces inflammatory genes through pus Box 7633, Raleigh, NC 27695. E-mail address: [email protected] TAK1–NF-kB and TAK1–AP-1 pathways in immune cells (7, 14– The online version of this article contains supplemental material. 16). TNF can activate caspase-dependent apoptosis through the Fas- Abbreviations used in this paper: BHA, butylated hydroxyanisole; CHX, cyclohex- associated death domain and procaspase 8 (also called FLICE) (17). imide; CM-H2DCFDA, 5-(and -6)-chloromethyl-2-dichlorodihydrofluorescein diac- TNF also activates NADPH oxidase, which generates reactive ox- etate; CT, control; Cyto, cytosolic fraction; IBD, inflammatory bowel disease; Nrf2, NF-E2–related factor 2; PD, potential difference; ROS, reactive oxygen species; ygen species (ROS) (18, 19). We recently reported that ablation of shRNA, short hairpin RNA; TAB, TGF-activated kinase 1-binding protein; TAK1, TAK1 causes hypersensitivity to TNF-induced apoptosis in kerati- TGF-b–activated kinase 1; tBHP, tert-butylhydroperoxide; TER, transepithelial elec- nocytes (20). In the epidermal-specific TAK1-deletion mice, the trical resistance. tissue damage in the skin is largely rescued by deletion of the Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 TNFR1 gene (11). However, in the intestinal epithelium, although www.jimmunol.org/cgi/doi/10.4049/jimmunol.0903587 4730 TAK1 REGULATES ROS IN THE INTESTINAL EPITHELIUM deletion of TNFR1 greatly reduces intestinal damage in neonatal 5 min. After removing the contents, the intestine was filled with 10 mM intestinal epithelial-specific TAK1-deletion mice, the mice sponta- EDTA in HBSS and incubated in PBS again for 10 min. The contents were neously develop ileitis and colitis at approximately postnatal day 15 collected into tubes and centrifuged at 1200 rpm for 5 min. The resulting pellets containing predominantly epithelial cells were washed twice in cold (10). Thus, ablation in enterocyte-derived TAK1 signaling results in PBS. TNF-dependent and -independent intestinal damage. In the current study, we investigated the mechanism by which TAK1 prevents Immunoblot analyses TNF-dependent and -independent intestinal epithelial damage. Nuclear and cytoplasmic extracts from enterocytes and keratinocytes were prepared using a Nuclear Extract Kit (Active Motif, Carlsbad, CA). Pro- Materials and Methods teins from cell lysates were electrophoresed on SDS-PAGE and transferred to Hybond-P (GE Healthcare). The membranes were immunoblotted with Mice polyclonal Abs against NF-E2–related factor 2 (Nrf2; Santa Cruz Bio- Mice carrying a floxed Map3k7 allele (TAK1FL/FL) (7) were backcrossed to technology, Santa Cruz, CA), TAK1 (8), TAK1-binding
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