Thr Role of TIMP1 in B Cell Differentiation and Survival

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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.