Title

Role of Heme Oxygenase-l in Interleukin-l Induced Expression of Matrix Metalloproteinase-3 in Human Gingival Fibroblasts

Date of Award

7-2011

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Ruth C Borghaei, PhD

Second Advisor

Farzaneh Daghigh, PhD

Third Advisor

Marina D'Angelo, PhD

Fourth Advisor

Marcus Bell, PhD

Abstract

Periodontitis, a chronic inflammatory disease that affects the periodontium or supporting structures of the teeth, can lead to gingival recession, degradation of the alveolar bone, and tooth loss. Periodontitis is the most common cause of adult tooth loss in the U.S., with an estimated 1 in 3 adults suffering from some form and 10-15% of adults developing severe forms. In addition to its direct impact, periodontitis also contributes to the development of several other diseases, including cardiovascular disease, pre-term low birth weight, and diabetes. Although the primary function of heme 11l oxygenase-l (HO-l) is the breakdown of heme to carbon monoxide, iron, and biliverdin/bilirubin, it has also been shown to play an important role in wound repair and the resolution of inflammation .by mechanisms involving homeostatic regulation of the redox state of cells. Matrix metalloproteinase-3 (MMP-3) over-production is involved in tissue destruction associated with chronic inflammation, and is regulated by redoxsensitive transcription factors. A series of experiments were designed to determine to what extent the levels of HO-l mRNA and protein are regulated by interleukin-l (IL-l), in human gingival fibroblasts (HGF) isolated from individuals with or without periodontitis. We also wanted to detelmine whether HO-l induction influences basal or IL-l-induced expression of MMP-3. Results showed that HO-l mRNA was expressed in HGF cultures derived from patients with periodontitis and that mRNA levels were inhibited over 60% by IL-l at 6 and 12 hours (10 ng/ml, p < 0.05). Interestingly however, HO-l protein levels derived from patients with periodontitis as measured by ELISA were not decreased by IL-l, but the cell lines isolated from patients without periodontitis showed IL-l decreased HO-l protein levels by approximately 55% at 24 hours. Hemin induced HO-l mRNA and increased basal and IL-l induced expression of MMP-3 mRNA in some HGF cell lines. The mechanisms behind these effects and reasons for cell line variation require further study. However, these results may have impOliant implications that should be considered as the feasibility of therapeutic HO-l induction is evaluated.

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