Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins.
Normal tissue homeostasis requires a finely balanced interaction between phagocytic scavenger cells (such as monocytes and macrophages) that degrade senescent material and mesenchymal cells (such as fibroblasts and smooth muscle cells), which proliferate and lay down new extracellular matrix. Macrophages and monocytes express specific surface receptors for advanced glycosylation end products (AGEs), which are covalently attached adducts resulting from a series of spontaneous nonenzymatic reactions of glucose with tissue proteins. Receptor-mediated uptake of AGE-modified proteins induces human monocytes to synthesize and release cytokines (TNF and IL-1), which are thought to contribute to normal tissue remodeling by mechanisms not entirely understood. We now report that AGEs also induce human monocytes to generate the potent progression growth factor insulin-like growth factor I (IGF-I), known to stimulate proliferation of mesenchymal cells. After in vitro stimulation with AGE-modified proteins, normal human blood monocytes express IGF-IA mRNA leading to the secretion of IGF-IA prohormone. The signal for IGF-IA mRNA induction seems to be initiated via the monocyte AGE-receptor, and to be propagated in an autocrine fashion via either IL-1 beta or PDGF. These data introduce a novel regulatory system for IGF-I, with broad in vivo relevance, and provide an essential link to the chain of events leading from the spontaneously formed tissue AGEs, hypothesized to act as markers of protein senescence, to their replacement and to tissue remodeling by the locally controlled induction of growth factors.
Kirstein
M
M
Laboratory of Medical Biochemistry, Rockefeller University, New York 10021.
Aston
C
C
Hintz
R
R
Vlassara
H
H
D015870:Gene Expression; D006023:Glycoproteins / Q000502:physiology*; D006031:Glycosylation; D006801:Humans; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D009000:Monocytes / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D006023:Glycoproteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D010982:Platelet-Derived Growth Factor; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma