Analysis of the nature and sequence of cell-derived and environmental signals required for the development of the fully activated macrophage was the long-term goal of our original proposal. Significant progress has been made towards the elucidation of the cellular and molecular mechanisms which control the acquisition of specific cell surface markers and functions during macrophage development. This progress is largely attributable to the recent availability of highly purified and cloned cytokines (such as recombinant Colony Stimulating Factors and interferons) which were used in conjunction with macrophages derived from the endotoxin """"""""hyporesponsive"""""""" C3H/HeJ mouse strain. In the studies described herein, we will continue to utilize this extremely sensitive system to extend our original findings. We propose (1) to examine the potential role of two distinct species of colony stimulating factor, i.e., CSF-1 and GM-CSF, in the generation of macrophage heterogeneity; (ii) to analyze further the molecular mechanisms which underlie the induction and down-regulation of macrophage Fc receptor and Ia antigen expression, as well as modulation of the glucocorticoid receptor; (iii) to examine the differentiation signals which may underlie acquisition of endotoxin sensitivity in vivo and in vitro; (iv) to examine the role of macrophage-derived interferon in macrophage differentiation; (v) to define the intracellular signals required for the acquisition of different stages of cytokine-induced macrophage differentiation; and (vi) to assess the capacity of a unique cytokine fusion protein to induce macrophage differentiation. The characterization of the cytokines involved, as well as a delineation of the specific sequences 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 stimulate activation of hosts macrophages might benefit patients who have neoplasms or infections with intracellular pathogens. In contrast, the capacity to control macrophage activation, such that the production of toxic mediators is mitigated, may be beneficial to patients who suffer from chronic inflammatory diseases, such as rheumatoid arthritis, periodontal disease, or inflammatory bowel disease. Finally, an improved understanding of the relationships between the state of macrophage activation and endotoxin sensitivity might provide insights for the successful treatment of septic shock or other complications of Gram negative bacillary infections.
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