beta(2)-Microglobulin modified with advanced glycation end products delays monocyte apoptosis
Department of Medicine, Division of Rheumatology
Antibodies; Antigens, CD95; Antigens, Surface; Apoptosis; Cells, Cultured; Dinoprostone; Fas Ligand Protein; Glycosylation End Products, Advanced; Humans; Interleukin-1; Intracellular Membranes; Lysosomes; Macrophages; Membrane Glycoproteins; Monocytes; Receptors, Immunologic; Superoxides; Time Factors; Tumor Necrosis Factor-alpha; beta 2-Microglobulin
Musculoskeletal Diseases | Rheumatology | Skin and Connective Tissue Diseases
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.
DOI of Published Version
Kidney Int. 2001 Mar;59(3):990-1002. Link to article on publisher's site
Hou, Fan Fan; Miyata, Toshio; Boyce, Joshua; Yuan, Qian; Chertow, Glenn M.; Kay, Jonathan; Schmidt, Ann Marie; and Owen, William F. Jr., "beta(2)-Microglobulin modified with advanced glycation end products delays monocyte apoptosis" (2001). Rheumatology Publications and Presentations. 84.