Interleukin-1 (IL-1) stimulates production of gingival fibroblast metalloproteinases (e.g., collagenase, stromelysin (proteoglycanase)) and thereby has been linked to gingival soft tissue destruction associated with periodontitis. The intracellular biochemical events that link IL-1 gingival fibroblast receptor activation to metalloproteinase gene activation are poorly understood. It is likely that a number of proteins (e.g., pretranscriptional/post-transcriptional regulatory factors, enzymes involved in signal transduction) play key roles in the modulation of these metalloproteinases. Recent studies with synovial and gingival fibroblasts in culture have provided new insights on the molecular events associated with the IL-1 induction of cellular metalloproteinases. Based on these studies the specific aims of the present proposal are: (I) To obtain full length cDNA sequences for three novel IL-1 induced genes obtained from human gingival fibroblasts, characterize them and express their proteins, (2) To determine if/how protein products derived from these novel genes and two other genes (CREB/ATF-3) upregulated by IL-1, functionally bind to the promoter region of metalloproteinases and (3) To determine if these selected genes functionally participate in the IL-1 induction of metalloproteinases.
These aims will be accomplished by using: (a) human gingival fibroblast cultures, (b) structural and functional characterization of five genes (three novel (GF7,GF27 and (GF57) and two known (CREB and ATF-3)) isolated by differential screening, and (c) overexpression and underexpression (antisense) studies. These proposed in-vitro studies with human gingival fibroblasts offer a model system to provide fundamental molecular information on gene activation induced by IL-1, and thereby identifying events which are likely involved in the pathogenesis of periodontitis. Identification of such genes holds promise for better defining the molecular basis of connective tissue destruction in periodontitis. Consequently, an important therapeutic implication of the present proposal is that blockers of these IL-1 induced biochemical events could be useful clinically for the future treatment of periodontitis.
| Thornton, R D; Lane, P; Borghaei, R C et al. (2000) Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts. Biochem J 350 Pt 1:307-12 |
| Fowler Jr, M J; Neff, M S; Borghaei, R C et al. (1998) Induction of bone morphogenetic protein-2 by interleukin-1 in human fibroblasts. Biochem Biophys Res Commun 248:450-3 |
