Heterogeneous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis -: Implications for therapy
Heterogeneous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis -: Implications for therapy
复制标题
DOI：
10.1002/art.11044
复制
发表时间：
2003-07-01
影响因子：
--
通讯作者：
Foxwell, BM
中科院分区：
文献类型：
--
作者：
Andreakos, E;Smith, C;Foxwell, BM
目的：研究IκB激酶1（IKK - 1）和IKK - 2在调节核因子κB（NF - κB）活化以及肿瘤坏死因子α（TNFα）、白细胞介素 - 1β（IL - 1β）、IL - 6、IL - 8、血管内皮生长因子（VEGF）和基质金属蛋白酶（MMPs）在类风湿关节炎（RA）中的表达方面的潜在作用。
方法：使用表达β - 半乳糖苷酶、显性负性IKK - 1和IKK - 2或IκBα的重组腺病毒感染来自接受关节置换手术的RA患者的体外RA滑膜培养物和滑膜成纤维细胞，或来自健康志愿者的人皮肤成纤维细胞、人脐静脉内皮细胞（HUVECs）和单核细胞衍生的巨噬细胞。然后，检测它们对RA滑膜细胞自发或刺激诱导释放炎性细胞因子、VEGF和MMPs的影响。
结果：在巨噬细胞中，IKK - 2对于脂多糖（LPS）诱导的NF - κB活化或TNFα、IL - 6或IL - 8的产生不是必需的，但对于响应CD40配体、TNFα和IL - 1的这一过程是必不可少的。在滑膜成纤维细胞、皮肤成纤维细胞和HUVECs中，IKK - 2对于LPS诱导的NF - κB活化以及IL - 6或IL - 8的产生也是必需的。在RA滑膜细胞中，IKK - 2的抑制对自发的TNFα产生没有影响，但显著降低了IL - 1β、IL - 6、IL - 8、VEGF以及MMPs 1、2、3和13。
结论：我们的研究表明，IKK - 2对于RA中TNFα的产生不是必需的。然而，由于IKK - 2调节其他炎性细胞因子（IL - 1β、IL - 6和IL - 8）、VEGF以及MMPs 1、2、3和13的表达，这些因子参与RA关节的炎症、血管生成和破坏过程，因此它可能仍然是一个良好的治疗靶点。
Objective. To investigate the potential role of IkappaB kinase 1 (IKK-1) and IKK-2 in the regulation of nuclear factor kappaB (NF-kappaB) activation and the expression of tumor necrosis factor alpha (TNFalpha), as well as interleukin-1beta (IL-1beta), IL-6, IL-8, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), in rheumatoid arthritis (RA).Methods. Recombinant adenoviruses expressing beta-galactosidase, dominant-negative IKK-1 and IKK-2, or IkappaBalpha were used to infect ex vivo RA synovial membrane cultures and synovial fibroblasts obtained from patients with RA undergoing joint replacement surgery, or human dermal fibroblasts, human umbilical vein endothelialcells (HUVECs),and monocyte-derivedmacrophages from healthy volunteers. Then, their effect on the spontaneous or stimulus-induced release of inflammatory cytokines, VEGF, and MMPs from RA synovial membrane cells was examined.Results. IKK-2 was not required for lipopolysaccharide (LPS)-induced NF-kappaB activation or TNFa, IL-6, or IL-8 production in macrophages, but was essential for this process in response to CD40 ligand, TNFalpha, and IL-1. In synovial fibroblasts, dermal fibroblasts, and HUVECs, IKK-2 was also required for LPS-induced NF-kappaB activation and IL-6 or IL-8 production. In RA synovial membrane cells, IKK-2 inhibition had no effect on spontaneous TNFa production but significantly reduced IL-1beta, IL-6, IL-8, VEGF, and MMPs 1, 2, 3, and 13.Conclusion. Our study demonstrates that IKK-2 is not essential for TNFa production in RA. However, because IKK-2 regulates the expression of other inflammatory cytokines (IL-1beta, IL-6, and IL-8), VEGF, and MMPs 1, 2, 3, and 13, which are involved in the inflammatory, angiogenic, and destructive processes in the RA joint, it may still be a good therapeutic target.