Macrophage/monocyte receptor for nonenzymatically glycosylated protein is upregulated by cachectin/tumor necrosis factor.
Proteins of extracellular matrix undergo over time multiple reactions with glucose to form advanced glycosylation endproducts (AGEs) which are highly active in protein crosslinking, and have been implicated in tissue damage associated with aging and diabetes. A macrophage/monocyte receptor for AGE moieties mediates the uptake of AGE-modified proteins by a process that also induces cachectin/tumor necrosis factor (TNF) and IL-1 secretion. Reasoning that cytokines might regulate this AGE-receptor system, we have evaluated the effect of cachectin/TNF, IL-1, and IFN-gamma on AGE-protein processing. We report that cachectin/TNF induced a severalfold enhancement of binding, endocytosis, and degradation of AGE-BSA by both murine peritoneal macrophages and human blood monocytes in vitro, and that cachectin/TNF enhanced the rate of disappearance of AGE-modified red blood cells in vivo. IL-1 and IFN-gamma alone did not increase AGE processing, but IFN-gamma consistently enhanced cachectin/TNF-induced changes in AGE-receptor kinetics. Similar effects were induced by AGE-BSA and FFI-BSA, a chemically synthesized AGE, when used as macrophage stimulants, possibly via cachectin/TNF induction. All upregulatory responses were blocked by anticachectin/TNF monoclonal antibody. These data suggest that AGE-induced cachectin/TNF, in addition to influencing tissue regeneration and remodelling, may also normally regulate the disposal of tissue damaging AGE-proteins through an autocrine upregulation.
Vlassara
H
H
Laboratory of Medical Biochemistry, Rockefeller University, New York 10021.
Moldawer
L
L
Chan
B
B
D000818:Animals; D004705:Endocytosis; D006023:Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D006031:Glycosylation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D006023:Glycoproteins; D007093:Imidazoles; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D012710:Serum Albumin, Bovine; D007371:Interferon-gamma; C041306:2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole