Wagner S, Stegen C, Bouterfa H, Huettner C, Kerkau S, Roggendorf W, Roosen K, Tonn J C
Department of Neurosurgery, University of Wuerzburg, Germany.
J Neurooncol. 1998 Nov;40(2):113-22. doi: 10.1023/a:1006146405880.
Matrix metalloproteinases have been implicated to play a vital role in glioma invasion as they degrade extracellular matrix to facilitate the subsequent migration of tumor cells into the surrounding brain tissue. The cytokine Interleukin-10 (IL-10) was detected recently in glial tumors in vivo. Expression of specific IL-10 mRNA as well as blood serum levels of IL-10 in glioma patients increased with malignancy suggesting a functional role of IL-10 in glioma progression. Moreover, glioma cell migration in vitro was enhanced in the presence of IL-10. We therefore investigated the expression of the matrix metalloproteinases (MMPs) stromelysin-1 (MMP-3), 72-kDa collagenase (MMP-2), 92-kDa collagenase (MMP-9), matrilysin (MMP-7) and the human macrophage metalloelastase (MMP-12). In addition, a possible relation between exposure of glioma cells to IL-10 and invasiveness of these cells due to MMP expression was analyzed. Experiments with Matrigel coated Boyden chambers revealed a pronounced dose dependent effect of IL-10 on glioma invasiveness. The synthetic MMP-inhibitor Marimastat markedly reduced cell invasion in the Boyden chambers confirming the significance of MMPs in the process of invasion. Subsequently, the expression level of MMPs and the serine protease uPA was investigated in 7 glioma cell lines (U373, GaMG, U251, GHE, SNB19, U138 and D54) by RT-PCR. In all but one cell line no enhancement of MMP expression by IL-10 was detected. Matrilysin in U373 cells was the only protease found to be upregulated in the presence of IL-10 dependent on cell density. The present data suggest that IL-10 related effects on the invasive properties of the cell lines are not directly mediated by an upregulation of matrix metalloproteinase expression.
基质金属蛋白酶被认为在胶质瘤侵袭中起着至关重要的作用，因为它们可降解细胞外基质，以促进肿瘤细胞随后向周围脑组织的迁移。细胞因子白细胞介素-10（IL-10）最近在体内的神经胶质瘤中被检测到。神经胶质瘤患者体内特定IL-10 mRNA的表达以及血清中IL-10的水平随恶性程度增加，这表明IL-10在神经胶质瘤进展中具有功能性作用。此外，在IL-10存在的情况下，体外胶质瘤细胞的迁移增强。因此，我们研究了基质金属蛋白酶（MMPs）基质溶解素-1（MMP-3）、72 kDa胶原酶（MMP-2）、92 kDa胶原酶（MMP-9）、基质溶素（MMP-7）和人巨噬细胞金属弹性蛋白酶（MMP-12）的表达。此外，还分析了胶质瘤细胞暴露于IL-10与这些细胞因MMP表达而产生的侵袭性之间的可能关系。用基质胶包被的博伊登小室进行的实验显示，IL-10对胶质瘤侵袭具有明显的剂量依赖性效应。合成的MMP抑制剂马立马司他显著降低了博伊登小室中的细胞侵袭，证实了MMPs在侵袭过程中的重要性。随后，通过逆转录聚合酶链反应（RT-PCR）研究了7种胶质瘤细胞系（U373、GaMG、U251、GHE、SNB19、U138和D54）中MMPs和丝氨酸蛋白酶尿激酶型纤溶酶原激活物（uPA）的表达水平。除一个细胞系外，在所有细胞系中均未检测到IL-10对MMP表达的增强作用。U373细胞中的基质溶素是唯一一种在IL-10存在下根据细胞密度上调的蛋白酶。目前的数据表明，IL-10对细胞系侵袭特性的相关影响并非直接由基质金属蛋白酶表达上调介导。
