Thr Role of TIMP1 in B Cell Differentiation and Survival

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在正常B细胞和部分肿瘤B细胞中表达。TIMP-1的表达与生发中心b细胞的分化状态有关，并在特定阶段表达。TIMP-1诱导b细胞从成中心细胞分化到成中心细胞分化阶段。TIMP-1下调CD10、CD38、CD77和表面免疫球蛋白的表达，上调表面CD40、CD23的表达，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退出。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。白细胞介素-10 （IL-10）在正常淋巴样细胞和非霍奇金淋巴瘤中表达，是一种分化/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，但IL-10不诱导TIMP-1在B细胞中的表达。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。细胞凋亡抑制和诱导分化是TIMP-1所特有的，在没有活性IL-10的情况下发生。此外，IL-10诱导增殖。因此，TIMP-1通过诱导IL-10的表达，直接抑制细胞凋亡，间接刺激细胞增殖。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。

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.