Background. A local inflammatory reaction to beta (2)-microglobulin (beta (
2)m) amyloid deposits by monocytes/macrophages is a characteristic histolog
ic 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 apo
ptosis 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, mor
phology, and function examined over the subsequent four days.
Results. AGE-modified but not unmodified beta (2)m significantly delayed sp
ontaneous apoptosis of human peripheral blood monocytes in adherent and non
adherent cultures. The effect of AGE-beta (2)m on monocytes apoptosis was t
ime- and dose-dependent and was attenuated by a blocking antibody directed
against the human AGE receptor (RAGE). There was no difference in effect be
tween AGE-beta (2)m and that of AGE-modified human serum albumin. Culture o
f 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 cha
nges in morphology similar to those observed when monocytes differentiate i
nto macrophages. The cultured cells increased in size and vacuolization, an
d their content of beta -glucuronidase and acid phosphatase increased by 5-
to 10-fold at day 4. Expression of the monocyte-macrophage membrane antige
ns HLA DR, CD11b, and CD11c also increased at day 4. Although exhibiting ph
enotypic 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 monoc
ytes cultured with AGE-beta (2)m, but declined with time in cells cultured
with serum. Constitutive synthesis of tumor necrosis factor-alpha (TNF-alph
a), interleukin-1 beta (IL-1 beta) and prostaglandin E-2 (PGE(2) 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 inf
lammatory response, with predominant accumulation of monocytes/macrophages,
in DRA.