Abstract
Thrombomodulin (TM) is highly expressed in endothelial cells and acts as a natural anticoagulation factor to maintain circulation homeostasis. TM is an interesting molecule with many physiological functions, including anti-inflammation, anti-thrombosis, and carcinogenesis inhibition. TM can also be detected on the spinous layer of epidermal keratinocytes. However, the role of epidermal TM is still under investigation. In this study, we investigated keratinocyte TM expression and regulation in response to sub-cytotoxic ultraviolet B (UVB) irradiation. Oxidative stress was assessed with DCF and the results revealed that UVB irradiation significantly and dose-dependently augmented reactive oxygen species (ROS) production in HaCaT cells. In addition, low-dose UVB irradiation decreased TM mRNA and protein levels. Blocking ROS production and ERK activation prevented UVB-induced TM down-regulation. The nuclear p53 accumulation and TM promoter binding was observed within 3 h after UVB exposure. Small interfering RNA-mediated p53 knockdown disrupted the UVB-mediated TM protein down-regulation. Our study demonstrates that UVB irradiation results in ROS accumulation and ERK activation, which causes the nuclear p53 accumulation and TM promoter binding to inhibit TM expression. This study provides novel evidence demonstrating that p53 serves as a key regulator of keratinocyte TM expression.
Highlights
In normal human skin, thrombomodulin (TM) is expressed in the keratinocyte suprabasal spinous layers where keratinocytes start to differentiate and make extensive contacts with surrounding keratinocytes [1]
These results suggested that sublethal ultraviolet B (UVB) irradiation dosage down regulates TM activity and protein levels, which may be because of downregulation of transcription regulation in HaCaT cells
UVB Regulates TM Expression via ERK Phosphorylation and p53 Nuclear Accumulation To further investigate the mechanism of UVB irradiationinduced p53 nuclear up-regulation and subsequent binding to the TM promoter to suppress TM expression, we examined whether ERK activation and reactive oxygen species (ROS) might be involved in p53 nuclear localization after UVB irradiation
Summary
Thrombomodulin (TM) is expressed in the keratinocyte suprabasal spinous layers where keratinocytes start to differentiate and make extensive contacts with surrounding keratinocytes [1]. Previous reports suggest that skin TM may regulate keratinocyte differentiation and modulate fibroblast collagen production during cutaneous wound healing [2,3]. TM demonstrates anti-inflammatory properties on UV irradiationinduced cutaneous inflammation [4]. Burned areas of the skin that exhibited negative TM staining caused proinflammatory cytokine release [5]. Clinical studies revealed an inverse correlation between TM expression and skin disease progression [6,7,8]. TM is functionally active and plays crucial homeostatic roles in skin epidermis
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