TIMP-1 EXPRESSION BY NORMAL LYMPHOCYTES & IN LYMPHOID NE

金属蛋白酶的组织抑制剂（TIMP’s）是一个密切相关的蛋白家族，最初被描述为基质金属蛋白酶（MMPs）的抑制剂。我们已经证明，除了阻断MMP活性外，TIMPs还具有生长因子样活性，以独立于MMP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源自b细胞肿瘤的细胞系中表达。TIMP-1在这些细胞中的表达与MMP表达无关。TIMP-1的表达与分化状态相关，似乎在生发中心b细胞的特定阶段表达。TIMP-1诱导b细胞进一步分化为生发中心表型，这伴随着淋巴细胞的产生而发生。TIMP-1的表达也与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退出。TIMP-1上调存活抗原CD40并下调CD77的表达，CD77是一种中性糖脂，由易于进入程序性细胞死亡的B淋巴细胞亚群表达。TIMP-1上调Bcl-XL，但不影响Bcl-2或Mcl-1的表达。TIMP-1也不会改变NF-kB的细胞质水平，但会增加NF-kB抑制剂IkBa的表达。我们已经证实EBV诱导了b细胞中TIMP-1的表达，并正在研究其机制。白细胞介素-10 （IL-10）在非霍奇金淋巴瘤中表达，它作为一种协同生长因子。TIMP-1以非mmp依赖的方式诱导b细胞中IL-10的表达。IL-10对诱导细胞凋亡没有保护作用，也不能诱导b细胞进一步分化。这些作用是TIMP-1特异性的，并且在没有活性IL-10的情况下发生。在一项b细胞非霍奇金淋巴瘤的研究中，TIMP-1表达、组织学分级和IL-10表达之间存在高度相关性。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，并抑制PCD。此外，TIMP-1表达可能是非霍奇金淋巴瘤的不良预后因素。

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.