Regulation of the expression of Class II major histocompatibility complex (MHC) glycoproteins on the surface of murine macrophages plays a critical role in the generation and control of immune responsiveness. Biosynthesis and expression of these glycoproteins is subject to both positive and negative regulation by various environmental stimuli including bacterial lipopolysaccharide (LPS). The proposed research will be conducted to investigate the mechanism by which LPS modulates the biosynthesis and expression of Ia molecules on murine macrophages. We will evaluate such issues as: stem cell requirements, accessory cell involvement, elaboration of Ia inducing factors, and the direct effects of LPS on macrophages. We will test the following hypothesis to explain the induction of Ia expression by LPS: First, an Ia-inducing factor elaborated by the stimulation of a lymphocyte-like accessory cell(s) drives the production of Ia+ macrophages from bone marrow macrophage precursors. Second, LPS inhibits the conversion of Ia+ to Ia- macrophages. Both effects could act in concert to result in the accumulation of Ia- expressing macrophages at the site of an LPs-mediated inflammatory response. We will attempt to define the lineage, phenotype and function of the cells involved and the molecular nature of the active molecular intermediates. In general, we hope to further our understanding of the mechanisms by which infections produced by gram-negative bacteria and their products influence macrophage function and how immunity to microorganisms is generated and expressed.
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