title: 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-kappaB, 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-kappaB and STAT3 to DNA was also decreased significantly. Additionally, dexamethasone induced the transcription of the I kappaB-alpha gene suggesting that in the presence of dexamethasone, NF-kappaB quickly reassociates with newly synthesized I kappaB-alpha and markedly reduces the amount of NF-kappaB. 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-kappaB, STAT3, and AP-1 activities, and can highlight a possible molecular mechanism for the anti-inflammatory effects of glucocorticoids.
authors.affiliation: Department of Orthodontics, School of Dentistry, Temple University, Philadelphia, Pennsylvania 19140, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Reddy
authors.forename: M
authors.initials: M
authors.lastname: Tewari
authors.forename: Q A
authors.initials: QA
authors.lastname: Hamid
authors.forename: O C
authors.initials: OC
authors.lastname: Tuncay
authors.forename: D S
authors.initials: DS
authors.lastname: Tewari
mesh_terms: D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D017364:Collagenases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D005881:Gingiva / Q000201:enzymology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D016328:NF-kappa B; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D003907:Dexamethasone; D015500:Chloramphenicol O-Acetyltransferase; D017364:Collagenases