Monocyte recruitment is thought to be important in a number of processes in the oral cavity including bacteria-induced periapical inflammation and in tissue remodeling associated with tooth eruption. The recruitment of monocytes in a number of pathologic processes is thought to involve the production of chemotactic mediators that stimulate monocyte migration and the expression of vascular adhesion molecules that provide a substrate for monocyte movement. The mechanisms that control monocyte recruitment in developmental tissue remodeling are less well understood. Despite the progress identifying the basic mechanisms that underlie monocyte recruitment, there is little concrete evidence identifying the specific mediators involved. Monocyte chemoattractant protein-1 (MCP-1) is a likely candidate as an important mediator for monocyte recruitment. This is based on reports that MCP-1 is expressed during several different pathologic conditions with a chronic inflammatory component in vivo. Furthermore, two of the most potent inducers of MCP-1, in vitro, are IL-1 and TNF-a. Lastly, MCP-1 is among the most potent and efficacious of the chemotactic cytokines that are relatively specific for monocytes. These studies suggest, but do not prove, that it is a critical mediator in the development of a monocyte infiltrate. The Principal Investigator has recently demonstrated that expression of MCP-1 is high correlated with monocyte recruitment in the oral cavity, during periapical inflammation, and during developmentally regulated tissue remodeling that occurs with tooth eruption. The goal of this proposal is to determine whether MCP-1 expression is regulated by IL-1 and TNF in vivo, specifically in bacteria-induced periapical inflammation, and in developmentally regulated tooth eruption. This will be accomplished utilizing transgenic mice which have targeted mutations of the IL-1 and/or TNF receptors by examining mice that lack functional IL-1 receptor type I, TNF-receptors (p55 and p75), or mice that lack receptors to both IL-1 (type 1) and TNF (p55). These studies will test the hypothesis that MCP-1 and monocyte recruitment is dependent upon stimulation by IL-1 and/or TNF activity in bacteria-induced periapical inflammation and during tooth eruption. The applicant also proposes that MCP-1 is important in stimulating monocyte recruitment in both of these processes. This will be accomplished by quantifying changes in monocyte infiltration in transgenic mice that lack a functional MCP-1 gene compared with normal mice. The use of transgenic mice with null mutations in IL-1 receptors, TNF-receptors, and MCP-1 provides a unique opportunity to provide fundamental information regarding the basic events in these two important processes in the oral cavity.
