Mach F, Schönbeck U, Sukhova G K, Bourcier T, Bonnefoy J Y, Pober J S, Libby P
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1931-6. doi: 10.1073/pnas.94.5.1931.
Increasing evidence supports involvement of inflammation and immunity in atherogenesis. We report here that CD40 ligand (CD40L), an immunoregulatory signaling molecule heretofore considered largely restricted to recently activated CD4+ T lymphocytes, is expressed by human vascular endothelial cells (EC), smooth muscle cells (SMC), and human macrophages in vitro, and is coexpressed with its receptor CD40 on all three cells types in human atherosclerotic lesions in situ. Cultured human vascular EC, SMC, and human macrophages all constitutively expressed CD40L mRNA as well as protein. Stimulation with interleukin 1beta, tumor necrosis factor alpha, or interferon gamma increased surface levels and de novo synthesis of CD40L on all three cell types. CD40L expressed on EC, SMC, and macrophages exhibited biological activity, as it induced B7.2 expression on B cells. Human vascular SMC also constitutively expressed CD40, the receptor for CD40L, and through CD40 signaling, human recombinant CD40L induced expression of proinflammatory cytokines in these cells, identifying SMC as a target for CD40L. Human atherosclerotic lesions (n = 8) showed expression of immunoreactive CD40L on EC, SMC, and macrophages, while normal arterial tissues (n = 5) contained no CD40L. In atheroma CD40L+ cells often also expressed CD40. These observations establish human vascular EC, SMC, and human macrophages as a novel source of CD40L, and point to T cell-independent CD40 signaling, and a broader function of this pathway in regulation of nonimmune cells, as illustrated here by potential autocrine and paracrine activation during atherogenesis.
越来越多的证据支持炎症和免疫参与动脉粥样硬化的发生。我们在此报告，CD40配体（CD40L），一种迄今为止被认为主要局限于近期活化的CD4 + T淋巴细胞的免疫调节信号分子，在体外由人血管内皮细胞（EC）、平滑肌细胞（SMC）和人巨噬细胞表达，并在人动脉粥样硬化病变原位的所有三种细胞类型上与其受体CD40共表达。培养的人血管EC、SMC和人巨噬细胞均组成性地表达CD40L mRNA以及蛋白质。用白细胞介素1β、肿瘤坏死因子α或干扰素γ刺激可增加所有三种细胞类型上CD40L的表面水平和从头合成。在EC、SMC和巨噬细胞上表达的CD40L表现出生物学活性，因为它诱导B细胞上B7.2的表达。人血管SMC也组成性地表达CD40L的受体CD40，并且通过CD40信号传导，人重组CD40L诱导这些细胞中促炎细胞因子的表达，确定SMC为CD40L的靶标。人动脉粥样硬化病变（n = 8）显示EC、SMC和巨噬细胞上有免疫反应性CD40L的表达，而正常动脉组织（n = 5）不含CD40L。在动脉粥样瘤中，CD40L +细胞通常也表达CD40。这些观察结果确立了人血管EC、SMC和人巨噬细胞作为CD40L的新来源，并指出了不依赖T细胞的CD40信号传导，以及该途径在调节非免疫细胞中的更广泛功能，如此处所示的动脉粥样硬化发生过程中的潜在自分泌和旁分泌激活。
