Salubrinal acts as a Dusp2 inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis.
Salubrinal acts as a Dusp2 inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis.
复制标题
DOI：
10.1016/j.cellsig.2015.01.010
复制
发表时间：
2015-04
影响因子：
4.8
通讯作者：
Yokota H
中科院分区：
文献类型：
--
作者：
Hamamura K;Nishimura A;Chen A;Takigawa S;Sudo A;Yokota H
双特异性磷酸酶2 （Dusp2，又称活化细胞磷酸酶1，PAC1）在活化免疫细胞中高表达。我们在抗胶原抗体诱导的关节炎（CAIA）小鼠模型中检测了Dusp2的潜在抑制剂salubrinal是否能阻止免疫细胞中的炎症细胞因子表达和关节炎反应。Salubrinal是一种抑制真核生物翻译起始因子2α (eIF2α)去磷酸化的合成化学物质。在这项研究中，我们使用全基因组微阵列、qPCR和RNA干扰检测了salubrinal对炎症相关基因以及DUSP基因家族表达的影响。我们还通过临床和组织学评分评估了salubrinal对CAIA小鼠关节炎反应的影响。结果显示，salubrinal可降低巨噬细胞、T淋巴细胞和肥大细胞中炎症基因的表达。在lps激活的巨噬细胞以及PMA/离子霉素激活的T淋巴细胞和肥大细胞中，Dusp2被salubrinal抑制。此外，Dusp2的部分沉默下调了il - 1β和Cox2，并且salubrinal显著抑制了CAIA小鼠的炎症体征。总之，本研究提出了salubrinal通过抑制Dusp2治疗炎性关节炎（如RA）的新可能性。
Dual-specificity phosphatase 2 (Dusp2; also called phosphatase of activated cells 1, PAC1) is highly expressed in activated immune cells. We examined whether a potential inhibitor of Dusp2, salubrinal, prevents inflammatory cytokine expression in immune cells and arthritic responses in a mouse model of anti-collagen antibody-induced arthritis (CAIA). Salubrinal is a synthetic chemical that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). In this study, we examined the effects of salubrinal on expression of inflammation linked genes as well as a family of DUSP genes using genome-wide microarrays, qPCR, and RNA interference. We also evaluated the effects of salubrinal on arthritic responses in CAIA mice using clinical and histological scores. The results revealed that salubrinal decreased inflammatory gene expression in macrophages, T lymphocytes, and mast cells. Dusp2 was suppressed by salubrinal in LPS-activated macrophages as well as PMA/ionomycin-activated T lymphocytes and mast cells. Furthermore, a partial silencing of Dusp2 downregulated IL1β and Cox2, and the inflammatory signs of CAIA mice were significantly suppressed by salubrinal. Collectively, this study presents a novel therapeutic possibility of salubrinal for inflammatory arthritis such as RA through inhibition of Dusp2.
登录
查看更多内容
影响因子：
--
作者：
Agarwal, Sandeep K.
通讯作者：
Agarwal, Sandeep K.
影响因子：
4.1
作者：
Jung SM;Kim KW;Yang CW;Park SH;Ju JH
通讯作者：
Ju JH
影响因子：
4.8
作者：
Hamamura K;Chen A;Nishimura A;Tanjung N;Sudo A;Yokota H
通讯作者：
Yokota H
影响因子：
2.8
作者：
Bencsáth, M;Blaskovits, A;Borvendég, J
通讯作者：
Borvendég, J
影响因子：
14.8
作者：
Khachigian, Levon M.
通讯作者：
Khachigian, Levon M.