title: Endothelial STAT3 Activation Increases Vascular Leakage Through Downregulating Tight Junction Proteins: Implications for Diabetic Retinopathy.
abstract: Vascular inflammation is characteristic feature of diabetic retinopathy. In diabetic retina, a variety of the pro-inflammatory cytokines are elevated and involved in endothelial dysfunction. STAT3 transcription factor has been implicated in mediating cytokine signaling during vascular inflammation. However, whether and how STAT3 is involved in the direct regulation of the endothelial permeability is currently undefined. Our studies revealed that IL-6-induced STAT3 activation increases retinal endothelial permeability and vascular leakage in retinas of mice through the reduced expression of the tight junction proteins ZO-1 and occludin. In a co-culture model with microglia and endothelial cells under a high glucose condition, the microglia-derived IL-6 induced STAT3 activation in the retinal endothelial cells, leading to increasing endothelial permeability. In addition, IL-6-induced STAT3 activation was independent of ROS generation in the retinal endothelial cells. Moreover, we demonstrated that STAT3 activation downregulates the ZO-1 and occludin levels and increases the endothelial permeability through the induction of VEGF production in retinal endothelial cells. These results suggest the potential importance of IL-6/STAT3 signaling in regulating endothelial permeability and provide a therapeutic target to prevent the pathology of diabetic retinopathy. J. Cell. Physiol. 232: 1123-1134, 2017. © 2016 Wiley Periodicals, Inc.
authors: Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Jang-Hyuk
authors: JH
authors: Yun
authors: Department of Biomedical Sciences, Seoul National University College of Medicine, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.|Fight Against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
authors: Sung Wook
authors: SW
authors: Park
authors: Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Kyung-Jin
authors: KJ
authors: Kim
authors: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea.
authors: Jong-Sup
authors: JS
authors: Bae
authors: Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors: Eun Hui
authors: EH
authors: Lee
authors: Department of Neurosurgery, Seoul National University Hospital, Seoul, Republic of Korea.
authors: Sun Ha
authors: SH
authors: Paek
authors: Medical Research Institute, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
authors: Seung U
authors: SU
authors: Kim
authors: Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
authors: Sangkyu
authors: S
authors: Ye
authors: Department of Biomedical Sciences, Seoul National University College of Medicine, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.|Fight Against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea.
authors: Jeong-Hun
authors: JH
authors: Kim
authors: Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
authors: Chung-Hyun
authors: CH
authors: Cho
mesh_terms: D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000633:toxicity; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D062793:Occludin / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D062793:Occludin; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D005947:Glucose