Park Eun Jung, Kim Young Min, Chang Ki Churl
Department of Pharmacology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea; Department of Convergence Medical Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea.
Department of Pharmacology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea.
Arch Med Res. 2017 Jul;48(5):423-431. doi: 10.1016/j.arcmed.2017.10.007. Epub 2017 Oct 28.
High mobility group box 1 (HMGB1) plays an important role as a pro-inflammatory cytokine that regulates inflammation in various diseases. We hypothesized that hemin might reduce HMGB1 release through the induction of HO-1 in UVB-induced HaCaTs.
The effects of hemin on the release of HMGB1 in UVB exposure were evaluated. The mechanisms were investigated using various signal inhibitors and small interfering RNA techniques.
Treatment with hemin inhibited reactive oxygen species (ROS) in UVB-induced HaCaTs in a dose-dependent manner. HMGB1 release by UVB was significantly reduced by hemin, N-acetyl-cysteine and DPI (NADPH oxidase inhibitor). Hemin increased HO-1 induction followed by phosphorylation of AMPK in a time- and dose-dependent manner. Additionally, hemin significantly increased the NAD/NADH ratio in HaCaTs. The inhibitory effects of UVB-induced HMGB1 release by hemin were significantly reversed not only with pharmacological inhibitors of AMPK (compound c) or HO-1 (ZnPPIX) but also through transfection of small interfering RNAs (siRNAs) for AMPK or HO-1. Interestingly, hemin decreased phosphor-AMPK expression by HO-1 siRNA transfection, but it failed to induce HO-1 in AMPK siRNA-transfected cells, which suggested that HO-1 was involved in AMPK activation by hemin in HaCaT. Moreover, recombinant HMGB1 induced Snail and inhibited E-Cadherin in HaCaTs, whereas hemin reversed those effects through rHMGB1.
It is concluded that the increased activity of HO-1/AMPK and scavenging ROS are, at least in part, responsible for the inhibition of UVB-induced HMGB1 release in keratinocyte HaCaTs. Therefore, hemin may be a useful agent for preventing UVB-induced skin cancer.
高迁移率族蛋白B1（HMGB1）作为一种促炎细胞因子，在多种疾病的炎症调节中发挥重要作用。我们推测血红素可能通过诱导HO-1减少紫外线B（UVB）诱导的角质形成细胞（HaCaTs）中HMGB1的释放。
评估血红素对UVB照射下HMGB1释放的影响。使用各种信号抑制剂和小干扰RNA技术研究其机制。
血红素处理以剂量依赖性方式抑制UVB诱导的HaCaTs中的活性氧（ROS）。UVB诱导的HMGB1释放被血红素、N-乙酰半胱氨酸和DPI（NADPH氧化酶抑制剂）显著降低。血红素以时间和剂量依赖性方式增加HO-1的诱导，随后AMPK磷酸化。此外，血红素显著增加HaCaTs中的NAD/NADH比值。血红素对UVB诱导的HMGB1释放的抑制作用不仅被AMPK（化合物c）或HO-1（锌原卟啉IX）的药理学抑制剂显著逆转，还通过转染针对AMPK或HO-1的小干扰RNA（siRNAs）而逆转。有趣的是，HO-1 siRNA转染使血红素降低了磷酸化AMPK的表达，但在AMPK siRNA转染的细胞中它未能诱导HO-1，这表明HO-1参与了血红素在HaCaT中对AMPK的激活。此外，重组HMGB1在HaCaTs中诱导Snail并抑制E-钙黏蛋白，而血红素通过重组HMGB1逆转了这些作用。
得出结论，HO-1/AMPK活性增加和清除ROS至少部分负责抑制UVB诱导的角质形成细胞HaCaTs中HMGB1的释放。因此，血红素可能是预防UVB诱导的皮肤癌的有用药物。
