Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury
Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury
复制标题
DOI：
10.1073/pnas.0704421104
复制
发表时间：
2007-06-26
影响因子：
11.1
通讯作者：
Phinney, Donald G.
中科院分区：
文献类型：
--
作者：
Ortiz, Luis A.;DuTreil, Maria;Phinney, Donald G.
间充质干细胞（MSC）已被开发作为细胞载体来治疗各种疾病，但其治疗效果的机制仍然不确定。以前，我们报道了骨髓间充质干细胞抑制博莱霉素（BLM）诱导的小鼠肺内炎症和纤维化。MSC转录组的询问确定白细胞介素1受体拮抗剂（IL 1 RN）作为这种作用的潜在介质。分级分离研究表明，MSC是小鼠骨髓中IL 1 RN的主要来源，并且其表达仅限于独特的细胞亚群。此外，MSC条件培养基显示阻断IL-1 α依赖性T细胞系的增殖，并抑制体外活化巨噬细胞产生TNF-α。在小鼠中进行的研究表明，MSC给药比通过腺病毒感染或渗透泵递送的重组IL 1 RN更有效地抑制BLM诱导的肺中TNF-α、IL-1 α和IL 1 RN mRNA、支气管肺泡灌洗（BAL）中IL 1 RN蛋白的增加。液，以及淋巴细胞和中性粒细胞进入肺部的运输。因此，MSC通过阻断肺中两种基本的促炎细胞因子TNF-α和IL-1来保护肺组织免受BLM诱导的损伤。表达IL 1 RN的人MSC亚群的鉴定可能为治疗人类慢性炎性疾病提供新的细胞载体。
Mesenchymal stem cells (MSCs) have been exploited as cellular vectors to treat a wide array of diseases but the mechanisms responsible for their therapeutic effect remain indeterminate. Previously, we reported that MSCs inhibit bleomycin (BLM)-induced inflammation and fibrosis within the lungs of mice. Interrogation of the MSC transcriptome identified interleukin 1 receptor antagonist (IL1RN) as a potential mediator of this effect. Fractionation studies indicated that MSCs are the principal source of IL1RN in murine bone marrow and that its expression is restricted to a unique subpopulation of cells. Moreover, MSC-conditioned media was shown to block proliferation of an IL-1 alpha-dependent T cell line and inhibit production of TNF-alpha by activated macrophages in vitro. Studies conducted in mice revealed that MSC administration was more effective than recombinant IL1RN delivered via adenoviral infection or osmotic pumps in inhibiting BLM-induced increases in TNF-alpha, IL-1 alpha, and IL1RN mRNA in lung, IL1RN protein in bronchoalveolar lavage (BAL) fluid, and trafficking of lymphocytes and neutrophils into the lung. Therefore, MSCs protect lung tissue from BLM-induced injury by blocking TNF-alpha and IL-1, two fundamental proinflammatory cytokines in lung. Identification of IL1RN-expressing human MSC subpopulations may provide a novel cellular vector for treating chronic inflammatory diseases in humans.