title: Thrombomodulin promotes diabetic wound healing by regulating toll-like receptor 4 expression.
abstract: Keratinocyte-expressed thrombomodulin (TM) and the released soluble TM (sTM) have been demonstrated to promote wound healing. However, the effects of high glucose on TM expression in keratinocytes and the role of TM in diabetic ulcer remain unclear. In this study, we demonstrated that expressions of TM and Toll-like receptor 4 (TLR4) were both downregulated in high-glucose cultured human keratinocytes and in skin keratinocytes of diabetic patients. In addition, the wound-triggered upregulation of TM and sTM production was abolished in both high-glucose cultured human keratinocytes and streptozotocin-induced diabetic mouse skin. Furthermore, supplementation of recombinant sTM could increase TLR4 expression and promote cutaneous wound healing in both high-glucose cultured human keratinocytes and diabetic mice. However, in Tlr4-deleted mice, which exhibited delayed wound healing, the therapeutic benefit of recombinant sTM was abrogated. Moreover, our results showed that tumor necrosis factor-α (TNF-α) expression in keratinocytes was dose-dependently upregulated by glucose, and TNF-α treatment downregulated the expression of TM and TLR4. Taken together, high-glucose environment reduces the expression of TM and TLR4 in keratinocytes possibly through the action of TNF-α, and recombinant sTM can increase the TLR4 expression and promote wound healing under diabetic condition.
authors: Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Tsung-Lin
authors: TL
authors: Cheng
authors: Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan.
authors: Chao-Han
authors: CH
authors: Lai
authors: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Po-Ku
authors: PK
authors: Chen
authors: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Chia-Fong
authors: CF
authors: Cho
authors: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Yun-Yan
authors: YY
authors: Hsu
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Kuan-Chieh
authors: KC
authors: Wang
authors: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Wei-Ling
authors: WL
authors: Lin
authors: Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Bi-Ing
authors: BI
authors: Chang
authors: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Shi-Kai
authors: SK
authors: Liu
authors: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Yu-Ting
authors: YT
authors: Wu
authors: Department of Dermatology, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan.
authors: Chao-Kai
authors: CK
authors: Hsu
authors: Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: gyshi@mail.ncku.edu.tw.
authors: Guey-Yueh
authors: GY
authors: Shi
authors: Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: halnwu@mail.ncku.edu.tw.
authors: Hua-Lin
authors: HL
authors: Wu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D048909:Diabetes Complications / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000737:chemistry; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013311:Streptozocin / Q000737:chemistry; D018180:Thrombomodulin / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing
chemical_list: D011994:Recombinant Proteins; C495345:TLR4 protein, human; D018180:Thrombomodulin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; D005947:Glucose
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