Macrophages are central to our innate immune responses to infection and malignancy. Bacterialproducts, such as Gram negative lipopolysaccharide (LPS), and cytokines, such as interferons (IFNs),program the expression of an array of pro- and anti-inflammatorygenes, that culminate in development of the """"""""fully activated"""""""" macrophage. Although fully activated macrophages exert microbicidal and tumoricidal effector functions, they have also been implicated in diseases characterized by excess cytokine production, e.g., Gram negative sepsis with accompanying Systemic InflammatoryResponse Syndrome. Thus, an understanding macrophage differentiationat the molecular level remains a significant area of investigation. Significant progress has been made towards elucidation of the subcellular mechanisms that regulate macrophage differentiation using an approach that integrates genetic, biochemical, immunologic, and molecular techniques to study macrophage differentiation at the level of gene expression. Purified LPSpreparations, LPS-mimetics and antagonists, recombinant cytokines, and inhibitors of specific signaling pathways, coupled with macrophages derived from the LPS-unresponsive C3H/HeJ mouse strain or mice with targeted mutations in genes required for LPSand/or IFN signaling, have enabled an analysisof the independent contributions of LPSand IFN to macrophage differentiation. In this proposal, we will: (i)utilize the LPS-mimetic,Taxol, as a novel probe to further analyze LPSsignaling mechanisms in macrophages; (ii)analyze the potential role of the newly identified TLRfamily of signal transducing proteins in LPS-stimulated macrophages; (iii) dissect mechanisms by which LPSand LPSpartial mimetics activate distinct, receptor-associated LPSsignaling pathways; and,(iv)ascertain the contribution of IFNs and Interferon Regulatory Factors (IRFs) in macrophage responses to LPS. Characterization of the network of intra- and intercellular signals that result in the development of the fully activated macrophage could provide novel therapeutic approaches for diseases in which activated macrophages have been shown to have beneficial or detrimental roles. The ability to activate host macrophages might benefit patients who have neoplasms, or infectionswith intracellular pathogens. In contrast, the ability to control macrophage activation, by mitigating overproduction of toxic mediators, may benefit patients who suffer from inflammatorysyndromes and may provide insights for the treatment of Gram negative sepsis.
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