Bioactivation of latent transforming growth factor β1 by Mycobacterium tuberculosis in human mononuclear phagocytes
Bioactivation of latent transforming growth factor β1 by Mycobacterium tuberculosis in human mononuclear phagocytes
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DOI：
10.1111/j.1365-3083.2005.01623.x
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发表时间：
2005-06-01
影响因子：
3.7
通讯作者：
Toossi, Z
中科院分区：
文献类型：
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作者：
Aung, H;Wu, M;Toossi, Z
生物活性转化生长因子β 1 （TGF β 1）已在肺部结核分枝杆菌（MTB）感染部位被发现；然而，其激活的潜在机制尚不清楚。通过对TGF β 1的酶联免疫斑点测定，我们发现人血液单核细胞（MN）和肺泡巨噬细胞（AM）在MTB刺激下产生具有生物活性的TGF β 1。然而，只有mtb刺激的MN在每个细胞的基础上增加了TGF β 1的产生。一种纤溶蛋白抑制剂bdellin降低了产生TGF β 1的MN的频率，表明纤溶蛋白途径在细胞因子的生物活化中起作用。mtb活化的MN中尿激酶纤溶酶原激活物受体（uPAR） mRNA及表面和可溶性uPAR （CD87）的表达均升高。然而，抗体中和uPAR单独抑制MN的生物活性TGF β 1。因此，越不成熟的MN，在结核病（TB）期间不断被招募到肺部，通过表达纤溶蛋白途径的成分，具有更高的生物激活TGF β 1的能力。结核分枝杆菌感染部位TGF β 1的过量产生和生物激活可能会破坏结核病期间宿主的免疫反应。
Biologically active transforming growth factor beta 1 (TGF beta 1) has been identified at sites of Mycobacterium tuberculosis (MTB) infection in the lung; however, the underlying mechanism(s) for its activation is not clear. Here using an enzyme-linked immunospot assay for TGF beta 1, we show that human blood monocytes (MN) and alveolar macrophages (AM) produce bioactive TGF beta 1 upon stimulation by MTB. However, only MTB-stimulated MN increased TGF beta 1 production on a per cell basis. The frequency of TGF beta 1-producing MN was reduced by an inhibitor of plasmin, bdellin, indicating a role for plasmin pathways in the bioactivation of cytokine. The expression of urokinase plasminogen activator receptor (uPAR) mRNA and both surface and soluble uPAR (CD87) was increased in MTB-activated MN. However, antibody neutralization of uPAR suppressed bioactive TGF beta 1 in MN alone. Thus, the more immature MN, which are continuously recruited to the lung during tuberculosis (TB), have a higher capacity to bioactivate TGF beta 1 by expression of components of the plasmin pathway. Excess production and bioactivation of TGF beta 1 at sites of MTB infection may undermine host immune responses during TB.