한빛사 논문
Min Ji Cho 1, Dong Gwang Lee 1, Jeong Woong Lee 1, Byungtae Hwang 1, Sung-Jin Yoon 2, Seon-Jin Lee 2, Young-Jun Park 2, Seung-Ho Park 2, Hee Gu Lee 3, Yong-Hoon Kim 4, Chul-Ho Lee 4, Jangwook Lee 1, Nam-Kyung Lee 1, Tae-Su Han 1, Hyun-Soo Cho 5, Jeong Hee Moon 6, Ga Seul Lee 6, Kwang-Hee Bae 7, Geum-Sook Hwang 8, Sang-Hak Lee 9, Sang J Chung 10, Sungbo Shim 11, Jaehyung Cho 12,13, Goo Taeg Oh 14, Young-Guen Kwon 15, Jong-Gil Park 1,16, Jeong-Ki Min 1,16
1Biotherapeutics Translational Research Centre.
2Environmental Disease Research Centre.
3Immunotherapy Convergence Research Centre.
4Laboratory Animal Resource Centre.
5Stem Cell Convergence Research Centre.
6Disease Target Structure Research Centre.
7Metabolic Regulation Research Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
8Integrated Metabolomics Research Group, Western Seoul Centre, Korea Basic Science Institute,150 Bugahyeon-ro, Seodaemun-gu, Seoul 03759, Republic of Korea.
9Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
10School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea.
11Department of Biochemistry, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju 28644, Republic of Kore.
12Division of Haematology, Department of Medicine.
13Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, U.S.A.
14Heart-Immune-Brain Network Research Centre, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
15Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
16Department of Bioscience, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
Min Ji Cho and Dong Gwang Lee contributed equally to this work.
Corresponding authors: Jong-Gil Park, Jeong-Ki Min
Abstract
Aims: The nuclear factor-κB (NF-κB) signalling pathway plays a critical role in the pathogenesis of multiple vascular diseases. However, in endothelial cells (ECs), the molecular mechanisms responsible for the negative regulation of the NF-κB pathway are poorly understood. In this study, we investigated a novel role for protein tyrosine phosphatase type IVA1 (PTP4A1) in NF-κB signalling in ECs.
Methods and results: In human tissues, human umbilical artery ECs, and mouse models for loss of function and gain of function of PTP4A1, we conducted histological analysis, immunostaining, laser-captured microdissection assay, lentiviral infection, small interfering RNA transfection, quantitative real-time PCR and reverse transcription-PCR, as well as luciferase reporter gene and chromatin immunoprecipitation assays. Short hairpin RNA-mediated knockdown of PTP4A1 and overexpression of PTP4A1 in ECs indicated that PTP4A1 is critical for inhibiting the expression of cell adhesion molecules (CAMs). PTP4A1 increased the transcriptional activity of upstream stimulatory factor 1 (USF1) by dephosphorylating its S309 residue and subsequently inducing the transcription of tumour necrosis factor-alpha-induced protein 3 (TNFAIP3/A20) and the inhibition of NF-κB activity. Studies on Ptp4a1 knockout or transgenic mice demonstrated that PTP4A1 potently regulates the interleukin 1β-induced expression of CAMs in vivo. In addition, we verified that PTP4A1 deficiency in apolipoprotein E knockout mice exacerbated high-fat high-cholesterol diet-induced atherogenesis with upregulated expression of CAMs.
Conclusion: Our data indicate that PTP4A1 is a novel negative regulator of vascular inflammation by inducing USF1/A20 axis-mediated NF-κB inactivation. Therefore, the expression and/or activation of PTP4A1 in ECs might be useful for the treatment of vascular inflammatory diseases.
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