Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Biomedical Laboratory Science, Cheongju University College of Health Science, Cheongju, Republic of Korea.
Cell Death Dis. 2017 Oct 26;8(10):e3148. doi: 10.1038/cddis.2017.550.
UV irradiation elicits acute inflammation in the skin by increasing proinflammatory cytokine production in keratinocytes. However, the downstream protein target(s) that link UV radiation to the activation of signaling pathways responsible for cytokine expression have not been fully elucidated. In this study, we report a novel role of transglutaminase 2 (TG2), a member of the TG enzyme family whose activities are critical for cornified envelope formation, in mediating UV-induced inflammation. Our results showed that TG2-deficient mice exhibited reduced inflammatory responses to UV irradiation, including reduced erythema, edema, dilation of blood vessels, inflammatory cell infiltration, and levels of inflammatory cytokines. Using primary mouse keratinocytes and HaCaT cells, we found that UV irradiation-induced cytokine production by activating TG2, but not by upregulating TG2 expression, and that ER calcium release triggered by the UV-induced activation of phospholipase C was required for TG2 activation. Moreover, TG2 activity enhanced p65 phosphorylation, leading to an increase in NF-κB transcriptional activity. These results indicate that TG2 is a critical mediator of cytokine expression in the UV-induced inflammatory response of keratinocytes, and suggest that TG2 inhibition might be useful for preventing UV-related skin disorders, such as photoaging and skin cancer caused by chronic UV exposure.
紫外线照射通过增加角质细胞中促炎细胞因子的产生，引发皮肤急性炎症。然而，将紫外线辐射与负责细胞因子表达的信号通路激活联系起来的下游蛋白靶标尚未完全阐明。在这项研究中，我们报告了转谷氨酰胺酶 2（TG2）的一个新作用，TG2 是 TG 酶家族的成员，其活性对于角蛋白形成是至关重要的，它在介导紫外线诱导的炎症中起作用。我们的结果表明，TG2 缺陷小鼠对紫外线照射的炎症反应减少，包括红斑、水肿、血管扩张、炎症细胞浸润和炎症细胞因子水平降低。使用原代小鼠角质细胞和 HaCaT 细胞，我们发现紫外线照射通过激活 TG2 而不是上调 TG2 表达来诱导细胞因子的产生，并且由紫外线诱导的磷脂酶 C 激活引起的 ER 钙释放是 TG2 激活所必需的。此外，TG2 活性增强了 p65 的磷酸化，导致 NF-κB 转录活性增加。这些结果表明，TG2 是角质细胞中紫外线诱导的炎症反应中细胞因子表达的关键介质，并表明 TG2 抑制可能有助于预防与紫外线相关的皮肤疾病，如慢性紫外线暴露引起的光老化和皮肤癌。
