Tumor necrosis factor alpha (TNF-alpha) has been shown to induce the production of interstitial collagenase by fibroblasts and chondrocytes. We investigated the role of TNF-alpha in collagenase gene expression by U937 monocyte/macrophage cells. Transcription of the TNF-alpha gene was observed after 0.5 h of phorbol myristate acetate (PMA) stimulation. Collagenase mRNA expression was not observed until 5-7 h of activation with PMA. TNF-alpha was detected in the culture supernatants 2-3 h before transcription of the collagenase gene. Neutralization of TNF-alpha protein with anti-TNF-alpha antibodies significantly reduced collagenase mRNA expression. Protein kinase C (PKC) and protein tyrosine kinase (PTK) inhibition essentially abolished both PMA-induced TNF-alpha protein secretion and collagenase mRNA expression. Collagenase gene expression induced by exogenous TNF-alpha in U937 cells stimulated with a suboptimal concentration of PMA was suppressed by PTK, but not PKC, inhibition. The pyrrolidine derivative of dithiocarbamate, a potent inhibitor of nuclear factor-kappa B (NF-kappa B) activation, resulted in a marked reduction in collagenase gene transcription, however, no reduction of TNF-alpha secretion was noted. Anti-TNF-alpha antibodies inhibited PMA-induced NF-kappa B activation. These observations demonstrate an important role for TNF-alpha in the autocrine regulation of collagenase gene expression by U937 cells. Additionally, TNF-alpha-induced PTK and NF-kappa B activation were important in collagenase gene expression in this cell line.