Guedez L, Stetler-Stevenson W G, Wolff L, Wang J, Fukushima P, Mansoor A, Stetler-Stevenson M
Flow Cytometry Unit, Hematopathology Section, National Cancer Institute, Bethesda, MD 20892-1500, USA.
J Clin Invest. 1998 Dec 1;102(11):2002-10. doi: 10.1172/JCI2881.
Cellular pathways for induction of programmed cell death (PCD) have been identified, but little is known about specific extracellular matrix processes that may affect apoptosis along those pathways. In this study, a series of Burkitt's lymphoma (BL) cell lines were assayed for their expression of tissue inhibitor of metalloproteinases (TIMP)-1. Results indicate that TIMP-1-positive BL lines show resistance to cold-shock-induced apoptosis. Furthermore, recombinant TIMP-1, but not TIMP-2 or a synthetic metalloproteinase inhibitor (BB-94), confers resistance to apoptosis induced by both CD95-dependent and -independent (cold shock, serum deprivation, and gamma-radiation) pathways in TIMP-1-negative BL lines. TIMP-1 suppression of PCD is not due to metalloproteinase inhibition, as reduction and alkylation of the TIMP-1 did not abolish this activity. Retroviral induction of TIMP-1 not only resulted in cell survival but also in continued DNA synthesis for up to 5 d in the absence of serum, while controls underwent apoptosis. This resistance to apoptosis is reversed by anti-TIMP-1 antibodies, demonstrating that secreted TIMP-1 is active in blocking apoptosis. Furthermore, TIMP-1 upregulation induced expression of Bcl-XL but not Bcl-2 as well as decreased NF-kappaB activity as compared with controls. These results demonstrate that TIMP-1 suppresses apoptosis in B cells and suggests a novel activity for TIMP-1 in tissue homeostasis.
诱导程序性细胞死亡（PCD）的细胞途径已被确定，但对于可能影响这些途径中细胞凋亡的特定细胞外基质过程却知之甚少。在本研究中，对一系列伯基特淋巴瘤（BL）细胞系进行了金属蛋白酶组织抑制剂（TIMP）-1表达的检测。结果表明，TIMP-1阳性的BL细胞系对冷休克诱导的细胞凋亡具有抗性。此外，重组TIMP-1而非TIMP-2或合成金属蛋白酶抑制剂（BB-94）能使TIMP-1阴性的BL细胞系对由CD95依赖性和非依赖性（冷休克、血清剥夺和γ辐射）途径诱导的细胞凋亡产生抗性。TIMP-1对PCD的抑制作用并非由于金属蛋白酶抑制，因为TIMP-1的还原和烷基化并未消除该活性。逆转录病毒诱导TIMP-1不仅导致细胞存活，而且在无血清的情况下持续进行DNA合成长达5天，而对照细胞则发生凋亡。抗TIMP-1抗体可逆转这种对细胞凋亡的抗性，表明分泌的TIMP-1在阻断细胞凋亡中具有活性。此外，与对照相比，TIMP-1上调诱导了Bcl-XL而非Bcl-2的表达，并降低了NF-κB活性。这些结果表明TIMP-1可抑制B细胞中的细胞凋亡，并提示TIMP-1在组织稳态中具有新的活性。
