TISSUE INHIBITOR OF METALLOPROTEINASE (TIMP)-1 INDUCES DIFFERENTIATION AND AN ANTIAPOPTOTIC PHENOTYPE IN GERMINAL CENTER B-CELLS

Tissue inhibitors of metalloproteinases (TIMPs) have been shown to be multifunctional factors. Contrasting with their enzyme-inhibitory acti vity, TIMPs also promote cell growth. Previously, we have reported an enhanced expression of TIMP-1 by normal reactive B cells and high-grad e lymphomas. In the present study, a series of Burkitt's lymphoma (BL) cell lines were analyzed for their expression of TIMP-1. TIMP-1 expre ssion correlates with upregulation of activation and survival markers. TIMP-1-negative cells express the phenotype associated with group I B k lines and Epstein-Barr virus (EBV)-negative, nonendemic BLs (CD10(+) , CD38(+), sIg(+), and CD77(+)). However, TIMP-1(+) BL lines showed gr oup II/III BL phenotype, downregulation of the above markers, and upre gulation and secretion of the activation marker CD23. Also, TIMP-1(+) cells have high levels of CD40 expression. To determine whether TIMP-1 is directly involved in the BL phenotype, an EBV-negative BL line JD3 8 was infected with timp-1-expressing retrovirus and analyzed. In the absence of EBV, upregulation of TIMP-1 is sufficient to induce the sam e phenotype seen in TIMP-1(+), EBV+ BL lines (CD10(-), CD38(-), sIg(-) , CD77(-), CD23(+), CD40 bright). This study not only suggests a role for TIMP-1 in BLs, but also supports its value as a prognostic factor.