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首页> 外文期刊>Journal of dermatological science >TLR4 and NLRP3 inflammasome activation in monocytes by N-propionyl cysteaminylphenol-maleimide-dextran (NPCMD)
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TLR4 and NLRP3 inflammasome activation in monocytes by N-propionyl cysteaminylphenol-maleimide-dextran (NPCMD)

机译：N-丙酰基半胱氨酰酚-马来酰亚胺-葡聚糖（NPCMD）在单核细胞中激活TLR4和NLRP3炎性体

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Background: N-propionyl cysteaminylphenol-maleimide-dextran (NPCMD) is a toxic tyrosinase substrate developed to treat melanoma. Objective: We investigated the effect of NPCMD on innate immune responses in monocytes. Methods: CD14+ monocytes and a monocytic cell line, THP-1, were stimulated with NPCMD in vitro. Cytokines in the culture supernatants were determined by ELISA and flow cytometry. Results: NPCMD stimulated CD14+ monocytes and THP-1 cells to secrete TNFα, IL-6 and IL-8, but not IL-10 or IL-12. TNFα secretion from THP-1 cells stimulated with NPCMD was inhibited by addition of an anti-TLR4 mAb in culture. Moreover, NPCMD stimulated production of pro-IL-1β in CD14+ monocytes and monocytic cell line THP-1 cells and activated the NLRP3-inflammasome, resulting in production of mature IL-1β. Use of ASC and NLRP3-deficient THP-1 cell lines established involvement of the NLRP3 inflammasome in an IL-1β secretion in treatment with NPCMD. Inhibition of IL-1β secretion by an endocytosis inhibitor, cytochalasin B, and a lysosomal enzyme cathepsin B inhibitor, CA-074 Me, suggested the involvement of lysosomal rupture and leakage of cathepsin B into the cytosol in NLRP3 activation by NPCMD. Conclusion: The immunopotentiating effect of NPCMD mediated by TLR4 and NLRP3 inflammasome activation could be useful for eliciting effective adaptive immune responses against melanoma and other tumors.
机译：背景：N-丙酰基半胱氨酰苯酚-马来酰亚胺-葡聚糖（NPCMD）是一种开发用于治疗黑色素瘤的有毒酪氨酸酶底物。目的：我们研究了NPCMD对单核细胞先天免疫应答的影响。方法：用NPCMD刺激CD14 +单核细胞和单核细胞系THP-1。通过ELISA和流式细胞术确定培养上清液中的细胞因子。结果：NPCMD刺激CD14 +单核细胞和THP-1细胞分泌TNFα，IL-6和IL-8，但不分泌IL-10或IL-12。通过在培养物中添加抗TLR4 mAb抑制了NPCMD刺激的THP-1细胞的TNFα分泌。此外，NPCMD刺激CD14 +单核细胞和单核细胞系THP-1细胞中前IL-1β的产生，并激活NLRP3-炎性小体，从而产生成熟的IL-1β。 ASC和NLRP3缺陷型THP-1细胞系的使用建立了NLRP3炎性小体参与NPCMD治疗时IL-1β分泌的作用。内吞抑制剂，细胞松弛素B和溶酶体酶组织蛋白酶B抑制剂CA-074 Me对IL-1β分泌的抑制表明，溶酶体破裂和组织蛋白酶B渗漏到NPCMD激活NLRP3中。结论：TLR4和NLRP3炎性小体激活介导的NPCMD的免疫增强作用可能有助于引发针对黑色素瘤和其他肿瘤的有效适应性免疫反应。

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