Regulation of 92-kD Gelatinase Release in HL-60 Leukemia Cells: Tumor Necrosis Factor-a! as an Autocrine Stimulus for Basal- and Phorbol Ester-Induced Secretion

Matrix metalloproteinase 9 ("P-9). also known as 92-kD type IV collagenaselgelatinase, is believed to play a critical role in tumor invasion and metastasis. Here, we report that MMP-9 was constitutively released from the human promyelocflic cell line HL-60 as determined by zymographic analysis. Tumor necrosis factor-a (TNF-a) enhanced the enzyme release threefold to fourfold and the protein kinase C (PKC) activator and differentiation inducer 12-0-tetradecanoylphorbol-13-acetate (TPA) eightfold to ninefold. Gelatinase induction by TNF-a and TPA was inhibited by actinomycin D or cycloheximide, indicating that de novo protein synthesis was required. Neutralizing monoclonal antibodies to TNF-a (anti-TNF-a) decreased the basal MMP-9 release of these cells. In addition, these antibodies also significantly interfered with the TPA-induced enzyme release. Agents that inhibit TNF-a expression in HL-60 cells, such as pentoxifylline and dexamethasone, completely abrogated both the constitutive and TPA-evoked MMP-9 release. Diethyldithio-