α1β1 integrin and interleukin-7 receptor up-regulate the expression of RANKL in human T cells and enhance their osteoclastogenic function
α1β1 integrin and interleukin-7 receptor up-regulate the expression of RANKL in human T cells and enhance their osteoclastogenic function
复制标题
DOI：
10.1111/j.1365-2567.2008.02858.x
复制
发表时间：
2008-11-01
期刊：
影响因子：
6.4
通讯作者：
Aoudjit, Fawzi
中科院分区：
文献类型：
--
作者：
Gendron, Steve;Boisvert, Marc;Aoudjit, Fawzi
活化的T细胞通过产生NF-κ B配体（RANKL）细胞因子的受体活化剂而参与与自身免疫性疾病（如类风湿性关节炎）相关的破骨细胞发育和骨丢失。然而，调节RANKL表达和诱导破骨细胞的细胞途径仍不清楚。在这项研究中，我们发现，在人效应CD 4（+）T细胞中，α 1 β 1整合素和白细胞介素（IL）-7受体（IL-7 R）的激活上调RANKL的表达和产生，但对干扰素-γ（T细胞介导的破骨细胞生成的抑制剂）的产生没有影响。因此，α 1 β 1整联蛋白和IL-7 R均增强这些细胞诱导人单核细胞形成破骨细胞的能力。此外，我们发现，同时激活效应CD 4（+）T细胞通过α 1 β 1整合素和IL-7 R协同增加RANKL的生产，并增强其破骨细胞的功能。我们还发现，虽然α 1 β 1整合素不能保护人效应CD 4（+）T细胞免受IL-2-撤药诱导的凋亡，但它确实增强了IL-7的促生存作用，进一步强调了α 1 β 1/IL-7 R协同效应的重要性。我们的研究结果共同确定了α 1 β 1整合素在T细胞中的新功能，并表明通过α 1 β 1整合素和IL-7 R激活效应CD 4（+）T细胞是T细胞依赖性破骨细胞生成的重要调控途径。进一步了解IL-7 R和α 1 β 1整合素促进T细胞介导的破骨细胞生成的机制将导致对与自身免疫性疾病相关的T细胞依赖性骨吸收的调节途径的新见解。
Activated T cells, through the production of the receptor activator of NF-kappa B ligand (RANKL) cytokine, have been implicated in the osteoclast development and bone loss that are associated with autoimmune diseases such as rheumatoid arthritis. However, the cellular pathways that regulate the expression of RANKL and the induction of osteoclasts are still unclear. In this study, we show that, in human effector CD4(+) T cells, activation of alpha 1 beta 1 integrin and interleukin (IL)-7 receptor (IL-7R) up-regulates the expression and production of RANKL but has no effect on the production of interferon-gamma, an inhibitor of T-cell-mediated osteoclastogenesis. Thus, both alpha 1 beta 1 integrin and IL-7R enhance the ability of these cells to induce the formation of osteoclasts from human monocytes. Furthermore, we found that simultaneous activation of effector CD4(+) T cells via alpha 1 beta 1 integrin and IL-7R synergistically increases the production of RANKL and enhances their osteoclastogenic function. We also show that, although alpha 1 beta 1 integrin does not protect human effector CD4(+) T cells from IL-2-withdrawal-induced apoptosis, it does enhance the pro-survival effect of IL-7, further emphasizing the importance of the alpha 1 beta 1/IL-7R synergistic effect. Together our results identify a new function of alpha 1 beta 1 integrin in T cells and suggest that activation of effector CD4(+) T cells through alpha 1 beta 1 integrin and IL-7R is an important regulatory pathway in T-cell-dependent osteoclastogenesis. Further understanding of the mechanisms by which IL-7R and alpha 1 beta 1 integrin promote T-cell-mediated osteoclastogenesis will lead to new insights into the regulatory pathways of T-cell-dependent bone resorption associated with autoimmune diseases.