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Bcl2l12 Contributes to Th2-Biased Inflammation in the Intestinal Mucosa by Regulating CD4+ T Cell Activities

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Bcl2l12 Contributes to Th2-Biased Inflammation in the Intestinal Mucosa by Regulating CD4+ T Cell Activities Bcl2L12 Contributes to Th2-Biased Inflammation in the Intestinal Mucosa by Regulating CD4+ T Cell Activities This information is current as Mao-Gang Li, Xiao-Yu Liu, Zhi-Qiang Liu, Jing-Yi Hong, of September 30, 2021. Jiang-Qi Liu, Cai-Jie Zhou, Tian-Yong Hu, Xiao-Jun Xiao, Pi-Xin Ran, Peng-Yuan Zheng, Zhi-Gang Liu and Ping-Chang Yang J Immunol published online 8 June 2018 http://www.jimmunol.org/content/early/2018/06/07/jimmun Downloaded from ol.1800139 Supplementary http://www.jimmunol.org/content/suppl/2018/06/07/jimmunol.180013 Material 9.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 30, 2021 • 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 Errata An erratum has been published regarding this article. Please see next page or: /content/203/6/1675.full.pdf /content/205/5/1473.full.pdf 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 © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published June 8, 2018, doi:10.4049/jimmunol.1800139 The Journal of Immunology Bcl2L12 Contributes to Th2-Biased Inflammation in the Intestinal Mucosa by Regulating CD4+ T Cell Activities Mao-Gang Li,* Xiao-Yu Liu,* Zhi-Qiang Liu,*,†,‡ Jing-Yi Hong,* Jiang-Qi Liu,*,†,‡ Cai-Jie Zhou,x Tian-Yong Hu,*,† Xiao-Jun Xiao,* Pi-Xin Ran,{ Peng-Yuan Zheng,‖ Zhi-Gang Liu,* and Ping-Chang Yang* The Th2-biased inflammation and immune deregulation play a critical role in the pathogenesis of ulcerative colitis (UC). Recent studies indicate that the Bcl2-like protein 12 (Bcl2L12) is associated with immune deregulation of UC. This study aims to investigate the role of Bcl2L12 in the induction of aberrant Th2-biased inflammation. In this study, peripheral blood samples were collected from patients with inflammatory bowel disease. The Th2 cell activities were analyzed by flow cytometry, real-time quantitative RT- PCR, and Western blotting. Mice with Bcl2L12-knockout CD4+ T cells were used in the experiments. The results showed that the expression of Bcl2L12 was detected in peripheral CD4+ T cells, which was significantly higher in UC patients than in healthy Downloaded from subjects. A positive correlation between the expression of Bcl2L12 and Th2 cytokines was detected in CD4+ T cells from UC patients. Naive CD4+ T cells with Bcl2L12 overexpression were prone to differentiate into Th2 cells. Mice with Bcl2L12 deficiency failed to induce the Th2-biased inflammation in the intestine. Bcl2L12 bound GATA3 to form a complex to enhance the binding between GATA3 and the Il4 promoter to enhance the expression of IL-4 in CD4+ T cells. CD4+ T cells with Bcl2L12 overexpression were resistant to apoptosis. In conclusion, the Bcl2L12 is a critical factor in the induction of aberrant Th2 polarization by upregulating Th2 responses and downregulating Th2 cell apoptosis. Bcl2L12 may be a novel therapeutic target in the management http://www.jimmunol.org/ of the disorders with Th2-biased inflammation. The Journal of Immunology, 2018, 201: 000–000. nflammatory bowel disease (IBD) is a chronic inflammatory have been recognized in IBD patients. Published data show that disease in the intestine, including ulcerative colitis (UC) and both Th1 and Th2 responses play roles in the inflammation of I Crohn disease (CD), which are two subtypes. The patho- IBD. Profound infiltration of Th1 or Th2 cells can be found in the genesis of IBD is not fully understood (1). The skewed immune IBD intestinal mucosa (4). These Th1 or Th2 cells are highly responses to commensal microbes (2) or food components (3) activated, producing high amounts of Th1, Th2, or Th17 cytokines (5). Yet, factors initiating the skewed immune cell differentiation by guest on September 30, 2021 and cytokine overproduction in the intestinal tissue of IBD pa- *Research Center of Allergy and Immunology, Shenzhen University School of Med- tients are not fully understood. icine, Shenzhen 518055, China; †Longgang ENT Hospital, Shenzhen ENT Institute, It is accepted that the dominant Th1 or Th17 response is involved Shenzhen 518116, China; ‡Brain-Body Institute, McMaster University, Hamilton, Ontario L8N 4A6, Canada; xLonggang Chinese Traditional Medical Hospital and in the pathogenesis of CD (6, 7). Dendritic cells in the intestinal Beijing University of Chinese Medicine Shenzhen Hospital, Shenzhen 518116, mucosa express TLR. Upon recognizing microbial stimuli by China; {State Key Laboratory of Respiratory Disease, Guangzhou Medical Univer- ‖ TLR, dendritic cells express IL-12 to initiate the Th1 response by sity, Guangzhou 510120, China; and Department of Gastroenterology, The Fifth + Affiliated Hospital of Zhengzhou University, Zhengzhou 470000, China enhancing the expression of IFN-g in CD4 T cells. Both Th1 and Received for publication January 31, 2018. Accepted for publication May 9, 2018. Th2 responses are associated with the immune phenotypes of UC. This work was supported by the Innovation of Science and Technology Commission of The skewed Th2-dominant immune response is an important Shenzhen Municipality (Grants JCYJ20150403091931195, JCYJ20160422101725667, factor in the pathogenesis of UC. A portion of UC patients is CXZZ20140902151802864, and JCYJ20160429091935720) and the National Natural sensitized to food allergens. Treatment with specific allergen im- Science Foundation of China (Grants 81503623, 31400856, 31570932, 81571790, and 81501573). munotherapy attenuated the inflammation of UC (8, 9). Yet, how M.-G.L., X.-Y.L., Z.-Q.L., J.-Y.H., J.-Q.L., C.-J.Z., T.-Y.H., and X.-J.X. performed the skewed Th2-dominant immune response initiated in the in- experiments, analyzed data, and reviewed the manuscript. P.-C.Y., Z.-G.L., P.-X.R., testine still remains elusive. Published data indicate a Th2- and P.-Y.Z. organized the study and supervised experiments. P.-C.Y. designed the project and wrote the paper. dominant immune response in UC patients (8–12). Based on the available knowledge, how the skewed Th2 response occurs in UC Address correspondence and reprint requests to Dr. Ping-Chang Yang, Dr. Zhi-Gang Liu, or Dr. Peng-Yuan Zheng, Room 509, Building A7, Xili Campus, Shenzhen patients is unclear. University School of Medicine, 1066 Xueyuan Boulevard, Shenzhen 518055, China In recent studies, we observed that the Bcl2-like protein 12 (P.-C.Y. and Z.-G.L.), or Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 470000, China (P.-Y.Z.). E-mail addresses: (Bcl2L12) was associated with the skewed immune response in [email protected] (P.-C.Y.), [email protected] (Z.-G.L.), or [email protected] patients with UC (12) and allergic rhinitis (13). Bcl2L12 is a (P.-Y.Z.) member of the Bcl2 family belonging to the antiapoptotic mole- The online version of this article contains supplemental material. cules (14). Previous studies showed that Bcl2L12 could neutralize Abbreviations used in this article: AICD, activation-induced cell death; Bcl2L12, p53 to prevent glioma cell apoptosis (15). Based on the above Bcl2-like protein 12; CD, Crohn disease; IBD, inflammatory bowel disease; IP, immunoprecipitation; KO, knockout; LPMC, lamina propria mononuclear cell; information, we hypothesize that Bcl2L12 may be involved in the + MPO, myeloperoxidase; RNAi, RNA interference; RT-qPCR, real-time quantitative skewed Th2 response. In this study, we found that CD4 T cells PCR; shRNA, short hairpin RNA; SPT, skin prick test; UC, ulcerative colitis; WT, expressed Bcl2L12, which was higher in UC patients than in CD wild type. patients and healthy subjects. Bcl2L12 bound the GATA3 pro- Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 moter to enhance the binding of GATA3 and the Il4 promoter. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800139 2 Bcl2L12 CONTRIBUTES TO ABERRANT Th2 RESPONSE Mice with Bcl2L12-knockout (KO) CD4+ T cells failed to induce RT-qPCR + inflammation in the intestine. CD4 T cells with Bcl2L12 over- Cells were collected from relevant experiments. The total RNA was extracted expression were resistant to apoptosis. The results suggest that with the TRIzol reagents. The cDNA was synthesized with a reverse tran- Bcl2L12 may be a potential therapeutic target in the management scription kit following the manufacturer’s instructions. The samples were of Th2-biased inflammation. amplified in a quantitative PCR device with the SYBR Green Master Mix and the primers of IL-4 (59-AACGAGGTCACAGGAGAAGG-39 and 59-TCTG- CAGCTCCATGAGAACA-39), IFN-g (59-TTCTTCAGCAACAGCAAGGC- Materials and Methods 39 and 59-ACTCCTTTTCCGCTTCCTGA-39), and Bcl2L12 (59-TTCCGAG- Reagents TTCTATGCCCTGG-39 and 59-CCAGTTTACGATGCAGAGCC-39). The results were presented as fold change against the housekeeping gene b-actin The short hairpin RNA (shRNA) kit of Bcl2L12, Abs of Bcl2L12, IL-4, (59-GGAAATCGTGCGTGACATCA-39 and 59-GCCACAGGATTCCATA- CD3, and GATA3 were purchased from Santa Cruz Biotech (Santa Cruz, CCCA-39). CA). The fluorochrome-labeled Abs of CD3, CD4, IL-4, IL-5, IL-13, IFN-g, and TNF were purchased from BD Biosciences (Franklin Lakes, Western blotting NJ). The IL-2, ELISA kits of IL-4, IL-5, IL-13, and TNF were purchased from R&D Systems (Minneapolis, MN). The reagents for real-time The total proteins were extracted from the cells collected from relevant ex- quantitative PCR (RT-qPCR), Western blotting, molecular cloning, and periments, fractioned by SDS-PAGE, and transferred onto a PVDF mem- plasmid transfection were purchased from Invitrogen (Carlsbad, CA).
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