Involvement of β2-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis-associated amyloidosis. Induction of human monocyte chemotaxis and macrophage secretion of tumor necrosis factor-α and interleukin-1

T. Miyata, R. Inagi, Y. Iida, M. Sato, N. Yamada, O. Oda, K. Maeda, H. Seo

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Abstract

β2-Microglobulin (β2M) is a major constituent of amyloid fibrils in hemodialysis-associated amyloidosis (HAA), a complication of long-term hemodialysis. However, the pathological role of β2M in HAA remains to be determined. Recently, we demonstrated that β2M in the amyloid deposits of HAA is modified with advanced glycation end products (AGEs) of the Maillard reaction. Since AGEs have been implicated in tissue damage associated with diabetic complications and aging, we investigated the possible involvement of AGE-modified β2M (AGE-β2M) in the pathogenesis of HAA. AGE- and normal- β2M were purified from urine of long-term hemodialysis patients. AGE-β2M enhanced directed migration (chemotaxis) and random cell migration (chemokinesis) of human monocytes in a dose-dependent manner. However, normal-β2M did not enhance any migratory activity. AGE-β2M, but not normal-β2M, increased the secretion of TNF-α and IL-1β from macrophages. Similar effects were also induced by in vitro prepared AGE-β2M (normal- β2M incubated with glucose in vitro for 30 d). When TNF-α or IL-1β was added to cultured human synovial cells in an amount equivalent to that secreted from macrophages in the presence of AGE-β2M, a significant increase in the synthesis of collagenase and morphological changes in cell shape were observed. These findings suggested that AGE-β2M, a major component in amyloid deposits, participates in the pathogenesis of HAA as foci where monocyte/macrophage accumulate and initiate an inflammatory response that leads to bone/joint destruction.

Original languageEnglish
Pages (from-to)521-528
Number of pages8
JournalJournal of Clinical Investigation
Volume93
Issue number2
DOIs
Publication statusPublished - 1994 Jan 1
Externally publishedYes

Keywords

  • collagenase
  • cytokines
  • human synovial cell
  • long-term hemodialysis patient
  • monocyte/macrophage

ASJC Scopus subject areas

  • Medicine(all)

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