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.
| Guedez, Liliana; Martinez, Antonio; Zhao, Shumei et al. (2005) Tissue inhibitor of metalloproteinase 1 (TIMP-1) promotes plasmablastic differentiation of a Burkitt lymphoma cell line: implications in the pathogenesis of plasmacytic/plasmablastic tumors. Blood 105:1660-8 |
| Haviernik, Peter; Lahoda, Carisa; Bradley, Heath L et al. (2004) Tissue inhibitor of matrix metalloproteinase-1 overexpression in M1 myeloblasts impairs IL-6-induced differentiation. Oncogene 23:9212-9 |
