title: Epigallocatechin-3-gallate sensitizes IFN-γ-stimulated CD4+ T cells to apoptosis via alternative activation of STAT1.
abstract: Epigallocatechin-3-gallate (EGCG) exerts anti-inflammatory properties on immune cells and binds to CD4 molecules. However, the effects of EGCG on CD4(+) T cells remain largely unknown. Here, we found that EGCG enhanced IFN-γ-induced signal transducer and activator of transcription 1 (STAT1) activation in primary CD4(+) T cells from C57BL/6 mice and in a human leukemic CD4(+) T-cell line of Hut 78 cells, while it inhibited the classical pathway of IFN-γ signaling including activating phosphorylations of Janus kinase (JAK) 1, JAK2 and STAT3, forming interferon-γ activated sequence (GAS)-binding STAT1 homodimers, and producing pro-inflammatory chemokine (C-X-C motif) ligand 9 (CXCL9). CD4 blockade did not suppress the increase in IFN-γ-induced STAT1 activation in CD4(+) T cells by EGCG. Furthermore, activation of Src kinase was also triggered by IFN-γ plus EGCG in both Hut 78 and primary CD4(+) T cells. Interestingly, EGCG promoted apoptosis of CD4(+) T cells treated with IFN-γ. The increases in STAT1 activation and apoptosis induced by EGCG in IFN-γ-activated CD4(+) T cells were almost completely abolished by a selective Src family kinase inhibitor, SU6656. Moreover, EGCG alleviates CD4(+) CD45RB(hi) CD25(-) T cell transfer induced colitis with less accumulation of CD4(+) T cells in the colon. In conclusion, the present study reports an alternative activation of STAT1 via Src by EGCG in IFN-γ-activated CD4(+) T cells, which promotes the apoptosis of IFN-γ-activated CD4(+) T cells and contributes to the improvement of T cell-mediated colitis. Our findings suggest a novel role of EGCG in regulating IFN-γ signaling and controlling inflammation.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Xingxin
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Fenli
authors.initials: F
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Shu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China. Electronic address: yangsun@nju.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China. Electronic address: molpharm@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D002392:Catechin; D007371:Interferon-gamma; D053613:Janus Kinase 1; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D019061:src-Family Kinases; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse; C045651:epigallocatechin gallate; C507905:Jak1 protein, mouse
keywords: Apoptosis; EGCG; Inflammation; STAT1; Src