In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1

Cellular pathways for induction of programmed cell death (PCD) have been id entified, but little is known about spe chic extracellular matrix processes that may affect apoptosis along those pathways. In this study, a series of Burkitt's lymphoma (BL) cell lines were assayed for their expression of ti ssue inhibitor of metalloproteinases (TIMP)-1. Results indicate that TIMP-1 -positive BL lines show resistance to cold-shock-induced apoptosis, Further more, recombinant TIMP-1, but not TIMP-2 or a synthetic metalloproteinase i nhibitor (BB-94), confers resistance to apoptosis induced by both CD95-depe ndent and -independent (cold shock, serum deprivation, and gamma-radiation) pathways in TIMP-1-negative BL lines. TIMP-1 suppression of PCD is not due to metalloproteinase inhibition, as reduction and alkylation of the TIMP-1 did not abolish this activity, Retroviral induction of TIMP-1 not only res ulted in cell survival but also in continued DNA synthesis for up to 5 d in the absence of serum, while controls underwent apoptosis. This resistance to apoptosis is reversed by anti-TIMP1 antibodies, demonstrating that secre ted TIMP-1 is active in blocking apoptosis, Furthermore, TIMP-1 upregulatio n induced expression of Bcl-X-L but not Bcl-2 as well as decreased NF-kappa B activity as compared with controls. These results demonstrate that TIMP- 1 suppresses apoptosis in B cells and suggests a novel activity for TIMP-1 in tissue homeostasis.