Nemeth J A, Rafe A, Steiner M, Goolsby C L
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Exp Cell Res. 1996 Apr 10;224(1):110-5. doi: 10.1006/excr.1996.0117.
In addition to proteinase-inhibitory activities, growth-stimulatory activities have been described for all three known members of the tissue inhibitors of the metalloproteinase (TIMP) family, TIMP-1, TIMP-2, and ChIMP-3, believed to be the chicken homologue of TIMP-3. However, the mechanism by which the TIMPs stimulate cell growth is unclear. In this report we have demonstrated that rTIMP-2 was growth-stimulatory for human foreskin fibroblasts (HSF4, HSF43, HS68), lung adenocarcinoma cells (A549), human melanoma cells (WM115), and the Burkitt's lymphoma cell line RAMOS, and this stimulatory response was concentration-dependent, with the greatest stimulation occurring a 10-30 pM rTIMP-2 in [3H]thymidine incorporation assays and at 20-100 pM in cell growth assays. Normal human colon (18Co) and lung (37Lu) fibroblasts showed no response to rTIMP-2. [3H]Thymidine incorporation was inhibited by rTIMP-2 treatment in the nonadherent cell line HL60. These studies also demonstrated that for the cell types tested, TIMP-2 alone was insufficient for a growth stimulatory response requiring, at a minimum, the presence of insulin. In the absence of any "co-factor(s)," such as insulin, TIMP-2 treatment was inhibitory.
除了蛋白酶抑制活性外，金属蛋白酶组织抑制剂（TIMP）家族的所有三个已知成员，即TIMP-1、TIMP-2和ChIMP-3（被认为是TIMP-3的鸡同源物）都具有生长刺激活性。然而，TIMP刺激细胞生长的机制尚不清楚。在本报告中，我们已经证明重组TIMP-2（rTIMP-2）对人包皮成纤维细胞（HSF4、HSF43、HS68）、肺腺癌细胞（A549）、人黑色素瘤细胞（WM115）和伯基特淋巴瘤细胞系RAMOS具有生长刺激作用，并且这种刺激反应是浓度依赖性的，在[3H]胸苷掺入试验中，10 - 30 pM的rTIMP-2刺激作用最大，在细胞生长试验中，20 - 100 pM时刺激作用最大。正常人结肠（18Co）和肺（37Lu）成纤维细胞对rTIMP-2无反应。在非贴壁细胞系HL60中，rTIMP-2处理抑制了[3H]胸苷掺入。这些研究还表明，对于所测试的细胞类型，仅TIMP-2不足以产生生长刺激反应，至少需要胰岛素的存在。在没有任何“辅助因子”（如胰岛素）的情况下，TIMP-2处理具有抑制作用。
