beta(2)-Microglobulin modified with advanced glycation end products delays monocyte apoptosis

Kidney Int. 2001 Mar;59(3):990-1002. doi: 10.1046/j.1523-1755.2001.059003990.x.


Background: A local inflammatory reaction to beta(2)-microglobulin (beta(2)m) amyloid deposits by monocytes/macrophages is a characteristic histologic feature of dialysis-related amyloidosis (DRA). Since beta(2)m modified with advanced glycation end products (AGE-beta(2)m) is a major constituent of amyloid in DRA, we tested the hypothesis that AGE-beta(2)m affects apoptosis and phenotype of human monocytes.

Methods: Human peripheral blood monocytes were incubated with or without in vitro-derived AGE-beta(2)m, and their viability, extent of apoptosis, morphology, and function examined over the subsequent four days.

Results: AGE-modified but not unmodified beta(2)m significantly delayed spontaneous apoptosis of human peripheral blood monocytes in adherent and nonadherent cultures. The effect of AGE-beta(2)m on monocytes apoptosis was time- and dose-dependent and was attenuated by a blocking antibody directed against the human AGE receptor (RAGE). There was no difference in effect between AGE-beta(2)m and that of AGE-modified human serum albumin. Culture of monocytes with AGE-beta(2)m did not alter membrane expression of Fas or Fas ligand. Monocytes cultured with AGE-beta(2)m underwent substantial changes in morphology similar to those observed when monocytes differentiate into macrophages. The cultured cells increased in size and vacuolization, and their content of beta-glucuronidase and acid phosphatase increased by 5- to 10-fold at day 4. Expression of the monocyte--macrophage membrane antigens HLA-DR, CD11b, and CD11c also increased at day 4. Although exhibiting phenotypic characteristics of macrophages, monocytes cultured with AGE-beta(2)m functioned differently than macrophages cultured with serum. Superoxide production in response to phorbol myristic acetate was maintained in monocytes cultured with AGE-beta(2)m, but declined with time in cells cultured with serum. Constitutive synthesis of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and prostaglandin E2 (PGE2) increased in monocytes cultured for four to six days with AGE-beta(2)m.

Conclusions: These findings support a novel role for AGE-modified proteins such as AGE-beta(2)m that may contribute to the development of a local inflammatory response, with predominant accumulation of monocytes/macrophages, in DRA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies / pharmacology
  • Antigens, Surface / analysis
  • Apoptosis / drug effects*
  • Cells, Cultured
  • Dinoprostone / metabolism
  • Fas Ligand Protein
  • Glycation End Products, Advanced / chemistry
  • Glycation End Products, Advanced / pharmacology*
  • Humans
  • Interleukin-1 / metabolism
  • Intracellular Membranes / enzymology
  • Lysosomes / enzymology
  • Macrophages / immunology
  • Membrane Glycoproteins / metabolism
  • Monocytes / drug effects*
  • Monocytes / metabolism
  • Monocytes / physiology*
  • Monocytes / ultrastructure
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / immunology
  • Superoxides / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism
  • beta 2-Microglobulin / pharmacology*
  • fas Receptor / metabolism


  • Antibodies
  • Antigens, Surface
  • FASLG protein, human
  • Fas Ligand Protein
  • Glycation End Products, Advanced
  • Interleukin-1
  • Membrane Glycoproteins
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Tumor Necrosis Factor-alpha
  • beta 2-Microglobulin
  • fas Receptor
  • Superoxides
  • Dinoprostone