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Glucocorticoids are potent immunosuppressants shown to be effective in the treatment of inflammatory diseases. Reportedly, they work, in part, by inhibiting cytokines and other transcription factors including AP-1. In this study we investigated the mechanisms of efficient repression of collagenase gene expression by dexamethasone in the human gingival fibroblast. Northern analyses showed that IL-1-dependent collagenase mRNA production was significantly decreased in the presence of dexamethasone. The influence of dexamethasone on the transcription factor NF-kB, STAT3, and AP-1 was investigated by using the gel mobility shift assay with nuclear extracts prepared from the cells grown in the presence of dexamethasone. We observed that in addition to AP-1, binding of NF-kB and STAT3 to DNA was also decreased significantly. Additionally, dexamethasone induced the transcription of the IkB-α gene suggesting that in the presence of dexamethasone, NF-kB quickly reassociates with newly synthesized IkB-α and markedly reduces the amount of NF-kB. CAT transfection studies utilizing collagenase promoter demonstrated a dose-dependent transcriptional inhibition of IL-1-induced gingival collagenase gene expression by dexamethasone. These data reveal that collagenase gene expression can be regulated by the impairment of IL-1-stimulated NF-kB, STAT3, and AP-1 activities, and can highlight a possible molecular mechanism for the anti-inflammatory effects of glucocorticoids.