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Blood, 1 January 2002, Vol. 99, No. 1, pp. 258-267
NEOPLASIA
Tissue inhibitor of metalloproteinases 1 is an autocrine and
paracrine survival factor, with additional immune-regulatory functions,
expressed by Hodgkin/Reed-Sternberg cells
Elisabeth Oelmann,
Hermann Herbst,
Michael Zühlsdorf,
Oliver Albrecht,
Annette Nolte,
Christiane Schmitmann,
Oliver Manzke,
Volker Diehl,
Harald Stein, and
Wolfgang E. Berdel
From the Departments of Medicine (Hematology/Oncology)
and Pathology, Westfaelische Wilhelms Universitaet Muenster; the
Department of Pathology, Freie Universitaet Berlin; and the Department
of Hematology and Oncology, University Hospital Koeln, Germany.
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.
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