Endocytic receptors on macrophages have been well characterized as a clearance mechanism for mannose-terminated glycoproteins. Expression of these receptors is exquisitely regulated by the functional state of the macrophage. Mannose receptors are absent on fresh monocytes, and activity is depressed following macrophage activation. Maturation in culture is accompanied by appearance of receptor activity, and treatment with glucocorticoids greatly enhances receptor function. A physiological role for the mannose receptor has been suggested to involve the regulation of extracellular levels of lysosomal hydrolases. This is supported by the observation that in every instance where receptor expression is low, extracellular hydrolase levels are high, and when receptor activity is depressed, enzymes are increased. A mannose receptor has been recently described on both retinal pigmented epithelium and alveolar type II epithelium in culture. Although a function for the epithelial receptor is not known, it is possible that the mannose receptor may serve a generalized function of clearance of extracellular lysosomal hydrolases. The primary goals of this proposal are to define the mechanisms of regulation of expression of the mannose receptor in macrophages, and to compare the biosynthetic and kinetic properties of the macrophage receptor to the recently discovered epithelial mannose receptor. Specifically, the effects of differentiation, steroids, activation agents, and glycosylation inhibitors on the regulation of mannose receptor expression in macrophages in vitro will be studied, and the properties of the epithelial cell mannose receptor will be compared to the known properties of the macrophage receptor. These studies will lead to a better understanding of the role of the mannose receptor in recognition, clearance, and trafficking of lysosomal enzymes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Pathobiochemistry Study Section (PBC)
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Vanderbilt University Medical Center
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Rinaldo, J E; Clark, M; Parinello, J et al. (1994) Nitric oxide inactivates xanthine dehydrogenase and xanthine oxidase in interferon-gamma-stimulated macrophages. Am J Respir Cell Mol Biol 11:625-30
Shepherd, V L; Cowan, H B; Abdolrasulnia, R et al. (1994) Dexamethasone blocks the interferon-gamma-mediated downregulation of the macrophage mannose receptor. Arch Biochem Biophys 312:367-74
Cowan, H B; Vick, S; Conary, J T et al. (1992) Dexamethasone up-regulates mannose receptor activity by increasing mRNA levels. Arch Biochem Biophys 296:314-20
Shepherd, V L; Tarnowski, B I; McLaughlin, B J (1991) Isolation and characterization of a mannose receptor from human pigment epithelium. Invest Ophthalmol Vis Sci 32:1779-84
Shepherd, V L; Abdolrasulnia, R; Garrett, M et al. (1990) Down-regulation of mannose receptor activity in macrophages after treatment with lipopolysaccharide and phorbol esters. J Immunol 145:1530-6
Shepherd, V L; Abdolrasulnia, R; Stephenson, J et al. (1990) Modulation of mannose receptor activity by proteolysis. Biochem J 270:771-6
Bozeman, P M; Hoidal, J R; Shepherd, V L (1988) Oxidant-mediated inhibition of ligand uptake by the macrophage mannose receptor. J Biol Chem 263:1240-7