Cytosolic dsDNA triggers apoptosis and pro‐inflammatory cytokine production in normal human melanocytes
Cytosolic dsDNA triggers apoptosis and pro‐inflammatory cytokine production in normal human melanocytes
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DOI：
10.1111/exd.12621
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发表时间：
2015-04
影响因子：
3.6
通讯作者：
Suiquan Wang;Dongyin Liu;W. Ning;A. Xu
中科院分区：
文献类型：
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作者：
Suiquan Wang;Dongyin Liu;W. Ning;A. Xu
大量证据提示病毒感染可能是白癜风发病的参与因素。然而，目前还不清楚病毒感染如何导致黑素细胞破坏。为了阐明病毒dsDNA对正常人黑素细胞的活力和细胞因子合成的影响并探讨其潜在机制，用poly（dA：dT）转染原代培养的正常人黑素细胞。结果表明，poly（dA：dT）在黑素细胞中引发凋亡而不是焦亡。通过RNA干扰敲低AIM 2或RIG-I部分减少了poly（dA：dT）诱导的LDH释放，表明两种核酸传感器都参与了黑素细胞死亡的过程。Poly（dA：dT）诱导促炎细胞因子基因的表达，包括IFN-β、TNF-α、IL-6和IL-8，而促炎细胞因子的产生被RIG-I siRNA抑制，但不被AIM 2 siRNA抑制。Poly（dA：dT）处理可增加p38、JNK和NFκB的磷酸化。因此，NFκB抑制剂Bay 11 - 7082和JNK抑制剂SP 600125阻断了除IFN-β以外的细胞因子基因的诱导。IL 6和IL 8的产生也被p38抑制剂SB 203580抑制。相反，聚（dA：dT）诱导的黑素细胞死亡仅被SP 600125降低。本研究提供了病毒感染后天然免疫反应导致白癜风黑素细胞破坏和免疫刺激的可能机制。
Considerable evidence implicates that viral infection might be a participant factor in the pathogenesis of vitiligo. However, it is still unclear how viral infection leads to the melanocyte destruction. To elucidate the effects of viral dsDNA on the viability and cytokine synthesis of normal human melanocytes and to explore the underlying mechanisms, primary cultured normal human melanocytes were transfected with poly(dA:dT). The results demonstrated that poly(dA:dT) triggered apoptosis instead of pyroptosis in melanocytes. Knocking down AIM2 or RIG‐I by RNA interference partially reduced the poly(dA:dT)‐induced LDH release, suggesting the involvement of both nucleic acid sensors in the process of melanocyte death. Poly(dA:dT) induced the expression of pro‐inflammatory cytokine genes including IFN‐β, TNF‐α, IL‐6 and IL‐8 as well, whereas the pro‐inflammatory cytokine production was suppressed by RIG‐I siRNA, but not by AIM2 siRNA. Poly(dA:dT) treatment increased the phosphorylation of p38 and JNK and NFκB. Accordingly, NFκB inhibitor Bay 11‐7082 and JNK inhibitor SP600125 blocked the induction of the cytokine genes except IFN‐β. The production of IL6 and IL8 was also suppressed by p38 inhibitor SB203580. On the contrary, the Poly(dA:dT)‐induced melanocyte death was only decreased by SP600125. This study provides the possible mechanism of melanocyte destruction and immuno‐stimulation in vitiligo by innate immune response following viral infection.