INTERACTIONS OF BACTERIAL LPS WITH EPIDERMAL DENDRITIC CELLS

点击翻译按钮获取中文摘要

The objective of this project is to understand the molecular mechanisms by which murine Langerhans cells (LC) respond to bacterial lipopolysaccharide (LPS), an environmentally ubiquitous and medically important bacterial molecule. The hypothesis to be tested is that LC have specific and sensitive mechanisms for binding, internalizing, and catabolizing LPS. The best characterized candidate receptor in the recognition-response system for lipopolysaccharide is CD14, a glycosylphosphatidylinositol-anchored protein on the surfaces of monocytes, macrophages, and neutrophils. Relevant preliminary data describe extensive experience by the investigators with LPS interactions with neutrophils and monocyte-macrophage, and many of these techniques will be used to study LPS-LC interactions. Recent studies in collaboration with Dr. Akira Takashima demonstrate that LPS has the capacity to modulate the immune function of an epidermal LC line (Dendritic Cell lin x552). Upon stimulation with LPS, x552 cells begin to exhibit mature features, including; a) elevated expression of MHC class II, CD80 and CD86, b) secretion of relatively large amount of IL-1-beta, IL-6, and TNF-alpha, and c) potent capacity to activate naive T cells in vitro as well as in vivo. Specific aims are: 1) To characterize the binding receptor(s) for LPS on LC. 2) To analyze the internalization and catabolism (deacylation) of LPS by LC. 3) To study the ability of lipid A partial structure to mimic or block LPS actions on LC. It is possible that related analogs of LPS could be useful clinically for modulating LC responses to cutaneous antigens. In addition, monophosphoryl lipid A is in clinical trails as an immunomodulator to prevent post-operative infections; understanding its interactions with LC might thus have clinical relevance in the near future.