Thr Role of TIMP1 in B Cell Differentiation and Survival

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在正常B细胞和某些肿瘤B细胞株中均有表达。TIMP-1的表达与分化状态有关，由生发中心B细胞的特定阶段表达。TIMP-1诱导B细胞进一步分化，从中心母细胞向中心细胞阶段分化。TIMP-1下调CD10、CD38、CD77和表面免疫球蛋白的表达，上调表面CD40和CD23的表达，同时诱导CD23的分泌。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。白介素10(IL-10)由正常淋巴样细胞和非霍奇金淋巴瘤细胞表达，在非霍奇金淋巴瘤中起分化/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，但IL-10不诱导B细胞表达TIMP-1。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。抑制细胞凋亡和诱导分化是TIMP-1所特有的，并且在缺乏活性IL-10的情况下发生。此外，IL-10还可诱导细胞增殖。因此，TIMP-1通过诱导IL-10的表达，直接抑制细胞凋亡，间接促进细胞增殖。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可诱导B细胞分化、增殖，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 normal B cells as well as some neoplastic B cell lines. TIMP-1 expression correlates with differentiation state and is expressed by a specific stage of germinal center B-cells. TIMP-1 induces further differentiation in B-cells from the centroblast to the centrocyte stage of differentiation. TIMP-1 down-regulates expression of CD10, CD38, CD77 and surface immunoglobulin as well as up-regulates surface CD40 and CD23, while inducing CD23 secretion. TIMP-1 inhibits cold shock, Fas, radiation and serum starvation induced apoptosis without causing withdrawal from cell cycle. 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. Interleukin-10 (IL-10) is expressed by normal lymphoid cells and non-Hodgkin's lymphomas, where it acts as a differentiation/growth factor. TIMP-1 induces IL-10 expression in B-cells in a non-MMP dependent manner but IL-10 does not induce B cell expression of TIMP-1. IL-10 does not protect the cells from induction of apoptosis nor induce further B-cell differentiation. Apoptosis inhibition and induction of differentiation are specific to TIMP-1 and occur in the absence of active IL-10. Furthermore, IL-10 induces proliferation. Therefore, TIMP-1 directly inhibits apoptosis and indirectly stimulates proliferation by inducing expression of 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 B-cell differentiation, proliferation and inhibits PCD. Furthermore, TIMP-1 expression may be a negative prognostic factor in non-Hodgkin's lymphoma.