Allopurinol induces innate immune responses through mitogen-activated protein kinase signaling pathways in HL-60 cells
Allopurinol induces innate immune responses through mitogen-activated protein kinase signaling pathways in HL-60 cells
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DOI：
10.1002/jat.3272
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发表时间：
2016-09-01
影响因子：
3.3
通讯作者：
Yokoi, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Nakajima, Akira;Oda, Shingo;Yokoi, Tsuyoshi
别嘌呤醇是一种黄嘌呤氧化酶抑制剂，是人类严重皮肤不良反应（SCAR）的常见原因，包括伴有嗜酸性粒细胞增多和全身症状的药疹、Stevens-Johnson综合征和中毒性表皮坏死松解症。虽然SCARs被怀疑是免疫介导的，但别嘌呤醇诱导的SCARs的机制仍不清楚。在这项研究中，我们研究了别嘌呤醇是否有能力在体外诱导先天性免疫反应，使用人树突状细胞（DC）样细胞系，包括HL-60，THP-1和K562，和人角质形成细胞系，HaCaT。在这项研究中，我们证明，别嘌呤醇治疗HL-60细胞显著增加白细胞介素-8，单核细胞趋化蛋白-1和肿瘤坏死因子的mRNA表达水平的时间和浓度依赖性的方式。此外，别嘌呤醇诱导丝裂原活化蛋白激酶（MAPK）的磷酸化，如c-Jun N-末端激酶和细胞外信号调节激酶，其调节DC中细胞因子的产生。此外，别嘌呤醇诱导的细胞因子表达的增加被MAPK抑制剂共同治疗抑制。总的来说，这些结果表明，别嘌呤醇具有通过活化MAPK信号通路在DC样细胞系中诱导先天性免疫应答的能力。这些结果表明，先天免疫反应诱导的别嘌呤醇可能参与了别嘌呤醇诱导的SCAR的发展。Copyright（c）2015 John Wiley & Sons，Ltd.别嘌呤醇是人类严重皮肤不良反应（SCARs）的常见原因。虽然SCARs被怀疑是免疫介导的，但别嘌呤醇诱导的SCARs的机制仍不清楚。在这项研究中，我们证明，别嘌呤醇治疗HL-60细胞显着增加促炎细胞因子，包括IL-8，MCP-1，和TNF α的mRNA水平，通过激活MAPK信号通路。这些结果表明，先天免疫反应诱导的别嘌呤醇可能参与了别嘌呤醇诱导的SCAR的发展。
Allopurinol, an inhibitor of xanthine oxidase, is a frequent cause of severe cutaneous adverse reactions (SCARs) in humans, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis. Although SCARs have been suspected to be immune-mediated, the mechanisms of allopurinol-induced SCARs remain unclear. In this study, we examined whether allopurinol has the ability to induce innate immune responses in vitro using human dendritic cell (DC)-like cell lines, including HL-60, THP-1 and K562, and a human keratinocyte cell line, HaCaT. In this study, we demonstrate that treatment of HL-60 cells with allopurinol significantly increased the mRNA expression levels of interleukin-8, monocyte chemotactic protein-1 and tumor necrosis factor in a time- and concentration-dependent manner. Furthermore, allopurinol induced the phosphorylation of mitogen-activated protein kinases (MAPK), such as c-Jun N-terminal kinase and extracellular signal-regulated kinase, which regulate cytokine production in DC. In addition, allopurinol-induced increases in cytokine expression were inhibited by co-treatment with the MAPK inhibitors. Collectively, these results suggest that allopurinol has the ability to induce innate immune responses in a DC-like cell line through activation of the MAPK signaling pathways. These results indicate that innate immune responses induced by allopurinol might be involved in the development of allopurinol-induced SCARs. Copyright (c) 2015 John Wiley & Sons, Ltd.Allopurinol is a frequent cause of severe cutaneous adverse reactions (SCARs) in humans. Although SCARs have been suspected to be immune-mediated, the mechanisms of allopurinol-induced SCARs remain unclear. In this study, we demonstrate that treatment of HL-60 cells with allopurinol significantly increased the mRNA levels of pro-inflammatory cytokines, including IL-8, MCP-1, and TNFa, through activation of MAPK signaling pathways. These results indicate that innate immune responses induced by allopurinol might be involved in the development of allopurinol-induced SCARs.