Inhibition of Gingival Collagenase Gene Expression by Dexamethasone

Abstract 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.