Tissue inhibitor of metalloproteinases 1 is an autocrine and paracrine survival factor, with additional immune-regulatory functions, expressed by Hodgkin/Reed-Sternberg cells.
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.
Oelmann
Elisabeth
E
Department of Medicine (Hematology/Oncology), Westfaelische Wilhelms Universitaet Muenster, Germany. elisao@uni-muenster.de
Herbst
Hermann
H
Zühlsdorf
Michael
M
Albrecht
Oliver
O
Nolte
Annette
A
Schmitmann
Christiane
C
Manzke
Oliver
O
Diehl
Volker
V
Stein
Harald
H
Berdel
Wolfgang E
WE
D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015870:Gene Expression; D006689:Hodgkin Disease / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008198:Lymph Nodes / Q000737:chemistry / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D012313:RNA / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D016539:Reed-Sternberg Cells / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics
D000906:Antibodies; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D012313:RNA; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1