TIMP-1 EXPRESSION BY NORMAL LYMPHOCYTES & IN LYMPHOID NE

金属蛋白酶组织抑制因子(TIMP‘s)是一类密切相关的蛋白质家族，最初被描述为基质金属蛋白酶抑制因子(MMPs)。我们已经证明，除了阻断基质金属蛋白酶的活性外，TIMPs还具有生长因子样活性，以一种独立于基质金属蛋白酶抑制活性的方式促进B细胞的生长。TIMP-1在反应性淋巴样细胞和B细胞肿瘤细胞系中均有表达。TIMP-1在这些细胞中的表达与基质金属蛋白酶的表达无关。TIMP-1的表达与分化状态有关，可能在生发中心B细胞的特定阶段表达。TIMP-1诱导B细胞进一步分化为伴随淋巴母细胞生成的生发中心表型。TIMP-1的表达与II/III组EBV潜伏期表型呈正相关。TIMP-1通过诱导活化标志物CD23的表达和分泌来影响B细胞的活化。TIMP-1抑制冷休克、Fas、辐射和血清饥饿诱导的细胞凋亡，而不引起细胞周期的退出。TIMP-1上调生存抗原CD40，下调CD77的表达，CD77是一种中性糖脂，由B淋巴细胞亚群表达，容易进入程序性细胞死亡。TIMP-1上调Bclxl的表达，但不影响Bcl2或Mcl-1的表达。TIMP-1也不改变核因子-kB的胞浆水平，但确实增加了核因子-kB抑制因子IkBA的表达。我们已经证明了EBV诱导B细胞表达TIMP-1，并正在研究其机制。白介素10(IL-10)在非霍奇金淋巴瘤中表达，在非霍奇金淋巴瘤中发挥协同生长因子的作用。TIMP-1以非基质金属蛋白酶依赖的方式诱导B细胞表达IL-10。IL-10不能保护细胞免于诱导凋亡，也不能诱导B细胞进一步分化。这些作用是TIMP-1所特有的，并且在缺乏活性IL-10的情况下发生。在一项B细胞性非霍奇金淋巴瘤的研究中，TIMP-1的表达与组织学分级和IL-10的表达高度相关。综上所述，TIMP-1通过一种新的机制诱导IL-10表达和B细胞分化，抑制PCD。此外，TIMP-1的表达可能是非霍奇金淋巴瘤的一个负面预后因素。

The tissue inhibitors of metalloproteinases (TIMP's) are a family of closely related proteins that were initially described as inhibitors of matrix metalloproteinases (MMPs). We have shown that in addition to blocking MMP activity, TIMPs also have growth factor-like activity, promoting growth in B-cells in a manner independent of MMP inhibitory activity. TIMP-1 is expressed by reactive lymphoid cells as well as cell lines derived from B-cell neoplasms. TIMP-1 expression in these cells is unrelated to MMP expression. TIMP-1 expression correlates with differentiation state and appears to be expressed by a specific stage of germinal center B-cells. TIMP-1 induces further differentiation in B-cells to the germinal center phenotype that occurs with the generation of lymphoblasts. TIMP-1 expression also correlates positively with Group II/III EBV latency phenotype. TIMP-1 affects B-cell activation by inducing expression and secretion of the activation marker CD23. TIMP-1 inhibits cold shock, Fas, radiation and serum starvation induced apoptosis without causing withdrawal from cell cycle. TIMP-1 up-regulates the survival antigen CD40 and down-regulates expression of CD77, a neutral glycolipid expressed by a subset of B lymphocytes that readily enter programmed cell death. TIMP-1 up-regulates Bcl-XL but does not affect Bcl-2 or Mcl-1 expression. TIMP-1 also does not modify cytoplasmic levels of NF-kB but does increase expression of the NF-kB inhibitor IkBa. We have shown that EBV induces expression of TIMP-1 in B-cells and are studying the meachnism. Interleukin-10 (IL-10) is expressed by non-Hodgkin's lymphomas, where it acts as a cooperative growth factor. TIMP-1 induces IL-10 expression in B-cells in a non-MMP dependent manner. IL-10 does not protect the cells from induction of apoptosis nor induce the further B-cell differentiation. These actions are specific to TIMP-1 and occur in the absence of active IL-10. In a study of B-cell non-Hodgkin's lymphomas there was a high degree of correlation between TIMP-1 expression, histologic grade and IL-10 expression. In summary, TIMP-1 induces IL-10 expression as well as B-cell differentiation and inhibits PCD by a novel mechanism. Furthermore, TIMP-1 expression may be a negative prognostic factor in non-Hodgkin's lymphoma.