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Th2 LCR is essential for regulation of Th2 cytokines and for allergic asthma
Lee, Gap Ryol 이화여자대학교 세포신호전달연구센터 2009 고사리 세포신호전달 심포지움 Vol. No.11
Previous studies have shown that Th2 cytokine genes are coordinately regulated by Th2 locus control region(LCR). To examine the in vivo function of Th2 LCR, we generated CD4-specific Th2 LCR deficient(cLCR KO) mice using Cre-LoxP recombination. The number of CD4 T cells in the cLCR KO mouse is comparable to that in wild type mice. The expression of Th2 cytokines was dramatically reduced in in vitro stimulated splenic naive CD4 T cells in either Th0 or Th2 polarizing conditions. Upon ovalbumin challenge in the mouse model of allergic asthma, cLCR KO mice showed marked reduction in the recruitment of eosinophils and lymphocytes in the bronchoalveolar larvage fluid, lung airway inflammation, mucus production, goblet cell hyperplasia. These results directly demonstrate that Th2 LCR is critically important in the regulation of Th2 cytokine genes and in the pathogenesis of allergic asthma.
Regulation of Th2 cytokine locus during T helper cell differentiation
Lee, Gap Ryol 이화여자대학교 세포신호전달연구센터 2007 고사리 세포신호전달 심포지움 Vol. No.9
Naive CD4+ T cells differentiate into Th1 or Th2 effector T cells upon antigenic stimulation by antigen-presenting cells. Th1 and Th2 cells perform distinct immune functions; Th1 cells mediate cellular immunity against intracellular bacteria and viruses, whereas Th2 cells enable humoral immunity and immunity against extracellular parasites. Th2 cytokine locus, which contains il4, il5 and il13 genes, undergoes structural and epigenetic changes during differentiation. Transgenic reporter assay shows that the Th2 cytokine locus is coordinately regulated by a locus control region (LCR) which is located in the intervening rad50 gene. Th2 LCR is composed of Th2 specific DNase I hypersensitive sites(DHSs) and undergoes chromatin modification during Th2 differentiation. One of the DHSs, RHS7, plays a critical role in regulating Th2 cytokine genes by establishing and maintaining the LCR-promoter interactions. Th2 LCR also interacts with IFN-locus by inter-chromosomal interactions in naive CD4 T cells. This study shed light on the mechanisms by which they regulate gene expression, revealing a new picture on how genes are regulated.
Lee, Jun Ho,Suh, Jae Hee,Choi, Soo Youn,Kang, Hyun Je,Lee, Hwan Hee,Ye, Byeong Jin,Lee, Gap Ryol,Jung, Seok Won,Kim, Chang Jae,Lee-Kwon, Whaseon,Park, Jiyoung,Myung, Kyungjae,Park, Neung Hwa,Kwon, Hyu BMJ Publishing Group 2019 Gut: journal of the British Society of Gastroenter Vol.68 No.2
<P><B>Objectives</B></P><P>Hepatocellular carcinoma (HCC) is a common cancer with high rate of recurrence and mortality. Diverse aetiological agents and wide heterogeneity in individual tumours impede effective and personalised treatment. Tonicity-responsive enhancer-binding protein (TonEBP) is a transcriptional cofactor for the expression of proinflammatory genes. Although inflammation is intimately associated with the pathogenesis of HCC, the role of TonEBP is unknown. We aimed to identify function of TonEBP in HCC.</P><P><B>Design</B></P><P>Tumours with surrounding hepatic tissues were obtained from 296 patients with HCC who received completion resection. TonEBP expression was analysed by quantitative reverse transcription–quantitative real-time PCR (RT-PCR) and immunohfistochemical analyses of tissue microarrays. Mice with TonEBP haplodeficiency, and hepatocyte-specific and myeloid-specific TonEBP deletion were used along with HCC and hepatocyte cell lines.</P><P><B>Results</B></P><P>TonEBP expression is higher in tumours than in adjacent non-tumour tissues in 92.6% of patients with HCC regardless of aetiology associated. The TonEBP expression in tumours and adjacent non-tumour tissues predicts recurrence, metastasis and death in multivariate analyses. TonEBP drives the expression of cyclo-oxygenase-2 (COX-2) by stimulating the promoter. In mouse models of HCC, three common sites of TonEBP action in response to diverse aetiological agents leading to tumourigenesis and tumour growth were found: cell injury and inflammation, induction by oxidative stress and stimulation of the COX-2 promoter.</P><P><B>Conclusions</B></P><P>TonEBP is a key component of the common pathway in tumourigenesis and tumour progression of HCC in response to diverse aetiological insults. TonEBP is involved in multiple steps along the pathway, rendering it an attractive therapeutic target as well as a prognostic biomarker.</P>
Expression Patterns of Immune Related Genes in Th1 and Th2 Cells Revealed by Microarray Analysis
Gap Ryol Lee 한국유전학회 2007 Genes & Genomics Vol.29 No.4
T helper cells play a distinct role in activating and regulating immune responses. Th1 cells mediate cellular immunity by activating macrophages, whereas Th2 cells mediate humoral immunity by activating B cells. The differentiation of Th1 and Th2 cells accompany drastic changes in immune function, cellular metabolism, gene expression, chromatin structure, and cell morphology. To search for more information on the immune functions of Th1 and Th2 cells, we examined a gene expression profile in immune related genes by microarray analysis. As expected many differentiation-specific cytokine, chemokine, and transcription factor genes are differentially expressed. I also discovered that a group of interferon-regulated genes is selectively expressed in Th1 cells, and that a group of immunoglobulin genes and various types of cell surface receptors are selectively expressed in Th2 cells. These studies extend the current understanding of immune function of T helper cells and find more molecules involved in the T helper cell differentiation.
The Balance of Th17 versus Treg Cells in Autoimmunity
MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.3
<P>T helper type 17 (Th17) cells and pTreg cells, which share a common precursor cell (the naïve CD4 T cell), require a common tumor growth factor (TGF)-β signal for initial differentiation. However, terminally differentiated cells fulfill opposite functions: Th17 cells cause autoimmunity and inflammation, whereas Treg cells inhibit these phenomena and maintain immune homeostasis. Thus, unraveling the mechanisms that affect the Th17/Treg cell balance is critical if we are to better understand autoimmunity and tolerance. Recent studies have identified many factors that influence this balance; these factors range from signaling pathways triggered by T cell receptors, costimulatory receptors, and cytokines, to various metabolic pathways and the intestinal microbiota. This review article summarizes recent advances in our understanding of the Th17/Treg balance and its implications with respect to autoimmune disease.</P>
Role of YY1 in long-range chromosomal interactions regulating Th2 cytokine expression.
Landes Bioscience 2014 Transcription Vol.5 No.1
<P>The molecular mechanism for chromatin remodeling and chromosomal interactions at the Th2 cytokine locus is not fully understood. Recently, we showed that transcription factor YY1 is critically involved in these events. This article discusses the possible roles of YY1 in these processes with particular emphasis on long-range chromosomal interactions.</P>
The transcription factor Batf3 inhibits the differentiation of regulatory T cells in the periphery
Lee, Wonyong,Kim, Hyeong Su,Hwang, Soo Seok,Lee, Gap Ryol Nature Publishing Group 2017 Experimental and molecular medicine Vol.49 No.11
<P>Naive CD4 T cells activated by antigen-presenting cells (APCs) undergo terminal differentiation in the periphery. Multiple mechanisms determine their fates, that is, whether they differentiate into conventional T (Tconv) cells or regulatory T (Treg) cells. The key event during Treg generation is expression of the transcription factor Foxp3, which is the lineage-determining regulator for Treg differentiation and function. Here we show that the transcription factor Batf3 acts as a fate-decision factor with respect to Tconv versus Tregs by restraining Treg differentiation. Batf3 was preferentially expressed in effector CD4 T cells but not in Treg cells, and ectopic expression of Batf3 inhibited Foxp3 induction. Batf3-deficient CD4 T cells favorably differentiated into Treg cells <I>in vitro</I> and in colonic lamina propria. Batf3 KO mice also showed enhanced Treg function in gut-associated immune disease models (for example, ovalbumin tolerance and inflammatory bowel disease models). Batf3 bound to the CNS1 region of the <I>Foxp3</I> locus and reduced expression of the gene. Thus, Batf3 is a transcriptional suppressor of Treg differentiation.</P>
Lee, Chun Geun,Hartl, Dominik,Lee, Gap Ryol,Koller, Barbara,Matsuura, Hiroshi,Da Silva, Carla A.,Sohn, Myung Hyun,Cohn, Lauren,Homer, Robert J.,Kozhich, Alexander A.,Humbles, Alison,Kearley, Jennifer The Rockefeller University Press 2009 The Journal of experimental medicine Vol.206 No.5
<P>Mouse breast regression protein 39 (BRP-39; Chi3l1) and its human homologue YKL-40 are chitinase-like proteins that lack chitinase activity. Although YKL-40 is expressed in exaggerated quantities and correlates with disease activity in asthma and many other disorders, the biological properties of BRP-39/YKL-40 have only been rudimentarily defined. We describe the generation and characterization of BRP-39<SUP>−/−</SUP> mice, YKL-40 transgenic mice, and mice that lack BRP-39 and produce YKL-40 only in their pulmonary epithelium. Studies of these mice demonstrated that BRP-39<SUP>−/−</SUP> animals have markedly diminished antigen-induced Th2 responses and that epithelial YKL-40 rescues the Th2 responses in these animals. The ability of interleukin13 to induce tissue inflammation and fibrosis was also markedly diminished in the absence of BRP-39. Mechanistic investigations demonstrated that BRP-39 and YKL-40 play an essential role in antigen sensitization and immunoglobulin E induction, stimulate dendritic cell accumulation and activation, and induce alternative macrophage activation. These proteins also inhibit inflammatory cell apoptosis/cell death while inhibiting Fas expression, activating protein kinase B/AKT, and inducing Faim 3. These studies establish novel regulatory roles for BRP-39/YKL-40 in the initiation and effector phases of Th2 inflammation and remodeling and suggest that these proteins are therapeutic targets in Th2- and macrophage-mediated disorders.</P>