ERYTHROID POTENTIATING ACTIVITY OF TISSUE INHIBITOR OF METALLOPROTEINASES ON THE DIFFERENTIATION OF ERYTHROPOIETIN-RESPONSIVE MOUSE ERYTHROLEUKEMIA CELL-LINE, ELM-I-1-3, IS CLOSELY RELATED TO ITS CELL-GROWTH POTENTIATING ACTIVITY

The erythroid-potentiating activity (EPA) of the tissue inhibitor of m etalloproteinase-1 (TIMP-1) was re-examined using ELM-I-1-3, a mouse e rythroleukemia cell line, which responded well to erythropoietin. Depl etion of pre-existing TIMP-1 from fetal calf serum in culture medium u sing monoclonal antibody suppressed erythropoietin-induced differentia tion as measured by the induction of hemoglobin, commitment assay and globin mRNAs. The removal of TIMP-1 also suppressed the proliferation of ELM-I-1-3 as measured by cell number and de novo DNA synthesis. The se changes were reversed by the addition of purified TIMP-1 to the cul ture medium. Anti-TIMP-1 antibody also blocked both hexamethylene bisa cetamide (HMBA)-induced erythroid differentiation and the proliferatio n of both ELM-I-1-3 and Friend erythroleukemia cells. Considering prev ious reports analyzing the chemical induction of Friend mouse erythrol eukemia cell differentiation, our results suggest that erythropoietin- or HMBA-induced erythroid differentiation might also be coupled with cell proliferation. Our H-3 thymidine-uptake experiment shows that TIM P-1 removal was also effective in the inhibition of cell growth of var ious other cell lines in addition to erythroleukemia cell lines. These results suggest that EPA action of TIMP-1 on erythroid leukemia cell lines is closely related to its activity to promote the cell growth of various cell lines and cells including erythroleukemia cell lines.