Synergistic benefit in inflammatory arthritis by targeting I kappaB kinase epsilon and interferon beta.
Synergistic benefit in inflammatory arthritis by targeting I kappaB kinase epsilon and interferon beta.
复制标题
DOI：
10.1136/ard.2008.095356
复制
发表时间：
2009-02
影响因子：
27.4
通讯作者：
Firestein GS
中科院分区：
文献类型：
--
作者：
Corr M;Boyle DL;Ronacher L;Flores N;Firestein GS
IκB激酶（IKK）相关激酶IKKε调节I型干扰素的表达和应答以及促炎介质的产生。我们研究了IKKε在关节炎中的作用及其增强被动小鼠K/BxN关节炎对系统性干扰素（IFN）β治疗反应的能力。给予IKKε−/−、IFNα~βR−/−和野生型小鼠K/BxN血清，并用聚肌苷酸（poly（I：C））、IFNβ或生理盐水处理。评估临床反应和组织学评分。通过定量PCR测量爪中的基因表达。采用ELISA法和微球芯片法检测血清白细胞介素1a受体激动剂（IL 1 Ra）和IL 10水平。如果在模型开始时同时给予致关节炎K/BxN血清和Toll样受体（TLR）3配体poly（I：C），则在野生型小鼠中几乎完全阻断关节炎，但在已建立的疾病中则不然。IFNα~βR缺陷小鼠关节炎病程加快，对poly（I：C）无反应。与杂合子小鼠相比，IKKε敲除小鼠的临床关节炎发生率适度降低。在野生型小鼠中无效的低剂量IFNβ显著降低IKKε敲除小鼠的临床关节炎。在患有关节炎的IKKε−/−小鼠中，关节趋化因子基因表达减少，分泌的IL 1 Ra（sIL 1 Ra）mRNA显著增加。在低剂量IFNβ处理的IKKε−/−小鼠中，血清IL 1 Ra水平升高。亚治疗剂量的IFNβ可增强IKKε缺乏的抗炎作用，可能是通过增加IL 1 Ra的产生和揭示抗趋化因子作用。低剂量IFNβ和IKKε抑制剂联合治疗可能改善单独使用任一药物的疗效，并为RA提供了一种新的治疗方法。
The IκB kinase (IKK)-related kinase IKKε regulates type I interferon expression and responses as well as proinflammatory mediator production. We examined the role of IKKε in arthritis and its ability to enhance the therapeutic response to systemic interferon (IFN) β therapy in passive murine K/BxN arthritis. IKKε−/−, IFNα~βR−/− and wild type mice were given K/BxN serum and treated with polyinosinic polycytidylic acid (poly(I:C)), IFNβ, or normal saline. Clinical response and histological scores were assessed. Gene expression in the paws was measured by quantitative PCR. Serum interleukin 1a receptor agonist (IL1Ra) and IL10 were measured by ELISA and multiplex bead array. Arthritis was almost completely blocked in wild type mice if arthritogenic K/BxN serum and the Toll-like receptor (TLR)3 ligand, poly(I:C), were coadministered at the onset of the model, but not in established disease. Mice deficient in IFNα~βR had an accelerated course of arthritis, and did not respond to poly(I:C). IKKε null mice had a modest decrease in clinical arthritis compared with heterozygous mice. Low doses of IFNβ that were ineffective in wild type mice significantly decreased clinical arthritis in IKKε null mice. Articular chemokine gene expression was reduced in the IKKε−/− mice with arthritis and secreted IL1Ra (sIL1Ra) mRNA was significantly increased. Serum levels of IL1Ra were increased in low dose IFNβ-treated IKKε−/− mice. Subtherapeutic doses of IFNβ enhance the anti-inflammatory effects of IKKε deficiency, possibly by increasing production of IL1Ra and unmasking the antichemokine effects. Combination therapy with low dose IFNβ and an IKKε inhibitor might improve efficacy of either agent alone and offers a novel approach to RA.
登录
查看更多内容
影响因子：
5.5
作者：
Tak, PP;'t Hart, BA;Breedveld, FC
通讯作者：
Breedveld, FC
DOI：
10.1099/vir.0.82603-0
发表时间：
2007-06
期刊：
The Journal of general virology
影响因子：
--
作者：
Adriaansen J;Fallaux FJ;de Cortie CJ;Vervoordeldonk MJ;Tak PP
通讯作者：
Tak PP
影响因子：
4.2
作者：
Lin, SL;Huang, CH;Yen, TS
通讯作者：
Yen, TS
影响因子：
56.9
作者：
tenOever, Benjamin R.;ng, Sze-Li Ng;Maniatis, Tom
通讯作者：
Maniatis, Tom
影响因子：
20.3
作者：
Lundberg, Anna M.;Drexler, Stefan K.;Foxwell, Brian M.
通讯作者：
Foxwell, Brian M.