Macrophages play a key role in host defense against invading pathogens and tumor growth. In the activated state, macrophages undergo extensive biochemical changes, many of which involve alterations in secretory rates and cell surface markers. At sites of inflammation, for example, the macrophages infiltrate the area and begin to flood the surrounding area with hydrolytic enzymes. It has recently been shown that macrophages in vivo and in vitro have the capacity to clear hydrolases from the extracellular milieu by receptor-mediated endocytosis. It has been suggested that this receptor (the mannose-specific receptor) is involved in regulating extracellular and intracellular levels of lysosomal enzymes. In addition, this receptor is closely modulated: when high levels of extracellular enzymes are required (following activation), the receptor activity declines; when low levels of enzymes result (following glucocorticoid treatment), receptor levels are high. Thus, the mannose receptor on macrophages offers a unique system to study receptor biosynthesis, turnover, and modulation during macrophage activation and treatment with glucocorticoids. The objective of this proposal is to study the mechanism of mannose receptor modulation on human macrophages in vitro, and to investigate the cell biological and biochemical alterations in receptor function following treatment with activating agents and dexamethasone. It is hoped that the experiments outlined in this proposal will help to define a physiological role for the mannose receptor, and aid in understanding the mechanism of modulation of macrophage function, in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022697-02
Application #
3134178
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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