Macrophage response to LPS in periodontal disease

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Current concepts suggest that the monocyte/macrophage response to bacterial LPS stimulation mediates, at least in part, the progression and severity of periodontal disease. In particular, elevated production of pro- inflammatory cytokines, such as IL-1beta and TNFalpha, and other inflammatory mediators (PGE2), appears to result in progression of attachment loss. In the diabetic patient, the intrinsic or constitutive cytokine response to LPS has been reported to be elevated above normal. The cytokine response associated with progression of periodontal disease is also markedly higher than in the non-diabetic population. The major LPS binding protein on macrophages is CD14. The cytokine response in macrophages to LPS is known to be mediated in part by CD14, although inhibition experiments using anti-CD14 antibody reveal only partial blocking. In addition, CD14 is a glycosylphosphatidylinositol (GPI) anchored protein without a signal across the cell membrane. A second class of LPS receptor has been hypothesized based on experiments identifying Toll like receptor (TLR) proteins, particularly TRL4, as LPS binding proteins and LPS binding to moesin induces both IL-1 and TNF production. Antibody to moesin ablates the CD14 mediated LPS response completely which is, in part, responsible for signal transduction of CD14 binding events. Our hypotheses is that moesin is a component of the CD14 /Toll LPS receptor complex. Further, that the expression and function of this molecule plays an important role in the pathogenesis of diabetes mellitus and it's complications, including periodontitis. Since the molecules involved in this response are not fully characterized, we will first pursue the characterization of LPS receptors and co-receptors in normal cells and then proceed to cells from the diabetic patient. The Specific Aims of this proposal, therefore, are to characterize the molecular structure/function relationship between CD14, LPS binding protein (LBP), Toll-like receptors (TRL4) and moesin.