Title

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

UMMS Affiliation

Department of Medicine, Division of Rheumatology

Date

3-1-2001

Document Type

Article

Medical Subject Headings

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

Disciplines

Musculoskeletal Diseases | Rheumatology | Skin and Connective Tissue Diseases

Abstract

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.

Rights and Permissions

Citation: Kidney Int. 2001 Mar;59(3):990-1002. Link to article on publisher's site

Comments

At the time of publication, Jonathan Kay was not yet affiliated with the University of Massachusetts Medical School.

Related Resources

Link to Article in PubMed

PubMed ID

11231354