Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. The production of inflammatory cytokines is a highly regulated process involving transcriptional and posttranscriptional mechanisms. At the posttranscriptional level, the presence of adenosine/uridine-rich elements (AREs) in the 3' untranslated region of many cytokine genes, including IL-6, TNF-a, and COX-2, targets the mRNA for rapid degradation. As a consequence, cytokine production is repressed. Tristetraprolin (TTP) is a zinc finger protein that binds to the ARE of cytokine mRNAs and enhances degradation of the mRNA. TTP is phosphorylated by the p38-MK2 pathway and may serve as a general mechanism of cytokine mRNA regulation. We have recently shown that LPS-induced IL-6 mRNA stability expression requires p38 signaling. Preliminary data for this proposal indicates that TTP transfected cells inhibit LPS-induced IL-6 expression. Based upon these data, we hypothesize that the mRNA decay enhancing properties of TTP may be exploited for potential anti-inflammatory purposes. In this proposal, the ability of TTP over-expression to decrease inflammation will be determined in vitro using gene targeted strategies in macrophages, and in vivo using experimental periodontitis models.
The specific aims are 1) to clarify the role of TTP on IL-6, TNF, and COX-2 mRNA expression and stability in vitro and 2) determine the impact of TTP in inflammatory and periodontal pathogen- initiated bone destruction in vivo using TTP-/- mice. These studies will establish the role of LPS-induced cytokine mRNA stability in inflammatory bone loss through selective mRNA decay targeting with TTP. Upon the accomplishment of these aims, subsequent studies will address the potential of TTP as a therapeutic strategy to control periodontal bone loss in small animal models. Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. These studies will establish the role of host immune proteins termed cytokines and the regulation of cytokines at the level of mRNA stability in inflammatory bone loss through selective mRNA decay targeting with a protein that regulates cytokine mRNA stability. Progress in understanding the role of posttranscriptional cytokine regulation in periodontal inflammation and bone loss may yield new possibilities for treatment of periodontal diseases and other chronic inflammatory diseases. ? ? ?
