Tissue inhibitor of metalloproteinases 1 is an autocrine and paracrine survival factor, with additional immune-regulatory functions, expressed by Hodgkin/Reed-Sternberg cells

Abstract

Tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 are proteins with proteinase-inhibiting and cytokine properties. TIMP-1 is active primarily in B cells and B-cell lymphomas, whereas TIMP-2 expression is restricted to T cells. The expression of TIMP-1 and TIMP-2 in lymph nodes from patients with Hodgkin disease (HD) and in Hodgkin-derived cell lines was investigated. In situ hybridization showed TIMP-1 RNA expression in 3% to 80% of Hodgkin/Reed-Sternberg (H/R-S) cells from 14 of 15 patients, with results in one patient being at the lowest detection limit; no expression of TIMP-2 in H/R-S cells; and only weak expression of TIMP-2 in reactive lymphoid tissue. Production of TIMP-1 protein by H/R-S cells was accordingly found on immunohistochemical analysis of lymph nodes from patients with HD. There was only low expression of matrix metalloproteinase (MMP)-2, which is mainly inhibited by TIMP-2; no expression of MMP-1 and MMP-3 in reactive lymphoid tissue; and no expression of these MMPs in H/R-S cells. Thus, TIMP-1 expression in lymph nodes was not correlated with metalloproteinase expression. Five of 7 Hodgkin-derived cell lines expressed TIMP-1 at the protein level. Only one of these cell lines expressed TIMP-2, at the lowest detection limit. TIMP-1 levels in plasma from patients with HD were within the same range as those in plasma from healthy controls. Recombinant human TIMP-1 inhibited induced cell death in Hodgkin-derived cell lines in vitro. TIMP-1 and TIMP-2 inhibited T-cell cytotoxicity against autologous cells presenting tumor-associated antigens and in allogeneic mixed lymphocyte cultures. Thus, TIMP-1, aside from its role in proteinase equilibrium, is an autocrine and paracrine survival factor for H/R-S cells and an immunosuppressive protein expressed in Hodgkin lymphomas.