Interleukin-1 (IL-1) stimulates production of metalloproteinases (MMPs, e.g. collagenase and stromelysin) by gingival fibroblasts, and has therefore been linked to soft tissue destruction associated with periodontitis. Although the precise mechanisms of IL-1 induction of MMP gene transcription have not been fully elucidated, evidence suggests that the effects of IL-1 are mediated by multiple transcription factors which may interact with the promoters in complex and cell specific ways.
The specific aims of this proposal are: 1) to identify transcription factors that specifically interact with the promoter regions of collagenase and stromelysin genes following IL-1 stimulation of gingival fibroblasts; 2) to determine the role(s) of factors identified in Specific Aim 1 in regulating transcription of collagenase and/or stromelysin genes in response to IL-1; and, 3) to further characterize, and clone or purify, any previously unknown factor(s) identified in Specific Aim 1 and shown to play a significant role in the regulation of MMP genes.
These specific aims will be accomplished through the use of DNAse footprinting/methylation interference and transient transfection experiments to systematically dissect the promoters in search of regulatory elements and binding complexes. In addition to providing important new information about how production of MMPs is regulated, these studies might also identify new potential targets for therapeutic agents for periodontitis.
| Borghaei, Ruth C; Rawlings Jr, P Lyle; Javadi, Masoud et al. (2004) NF-kappaB binds to a polymorphic repressor element in the MMP-3 promoter. Biochem Biophys Res Commun 316:182-8 |
| Borghaei, R C; Sullivan, C; Mochan, E (1999) Identification of a cytokine-induced repressor of interleukin-1 stimulated expression of stromelysin 1 (MMP-3). J Biol Chem 274:2126-31 |
| Borghaei, R C; Rawlings Jr, P L; Mochan, E (1998) Interleukin-4 suppression of interleukin-1-induced transcription of collagenase (MMP-1) and stromelysin 1 (MMP-3) in human synovial fibroblasts. Arthritis Rheum 41:1398-406 |
