Transforming growth factor-beta is involved in the pathogenesis of dialysis-related amyloidosis

Kidney Int. 2000 Feb;57(2):697-708. doi: 10.1046/j.1523-1755.2000.00892.x.


Background: Advanced glycation end product-modified beta2-microglobulin (AGE-beta2m) is an important component of dialysis-related amyloidosis (DRA). Its presence induces monocyte chemotaxis and the release of the proinflammatory cytokines through macrophage activation. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that also has chemotactic activity for monocytes at very low (0.1 to 10 pg/mL) concentrations and inhibits proinflammatory cytokine production of macrophages. In this study, we investigated the role of TGF-beta in the pathogenesis of DRA.

Methods: We performed an immunohistochemical study of DRA tissues (8 cases) to confirm the existence of TGF-betas and their receptors; we also performed a chemotaxis assay of human monocytes as well as enzyme-linked immunosorbent assay (ELISA) of TGF-beta1, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-1 receptor antagonist (IL-1Ra) in the supernatant of human monocyte-derived macrophage cell culture under varying conditions of incubation with TGF-beta1, AGE-beta2m, and TGF-beta1 antibody additions.

Results: There was positive staining for TGF-betas (types 1, 2, and 3) and their receptors (types I, II, and III) in infiltrated macrophages (CD68+), synovial lining cell, as well as vascular walls around amyloid deposition. AGE-beta2m also induced TGF-beta1 production by macrophages in a dose-dependent manner (410 +/- 80 pg/mL at 12.5 microg/mL, 621 +/- 62 pg/mL at 25 microg/mL, and 776 +/- 62 pg/mL at 50 microg/mL of AGE-beta2m). AGE-beta2m induced significant TNF-alpha and IL-1Ra production by macrophage. The addition of exogenous TGF-beta1 (0.1 to 10 ng/mL) decreased AGE-beta2m-induced TNF-alpha production and increased IL-1Ra production in a dose-dependent fashion. IL-1beta production was not effected by any experimental conditions. In chemotaxis assay, anti-TGF-beta1 antibody (0.1 to 10 microg/mL) attenuated AGE-beta2m-induced monocyte chemotaxis.

Conclusions: These results provide the first evidence to our knowledge for the presence of TGF-beta in DRA tissue, as well as the stimulatory action of AGE-beta2m on tissue macrophages. In turn, TGF-beta suppresses the proinflammatory activation of macrophages, suggesting a dual role for TGF-beta in the inflammatory process of DRA. These observations may provide a pathophysiologic link between TGF-beta and DRA.

Publication types

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

MeSH terms

  • Aged
  • Amyloidosis / etiology*
  • Amyloidosis / immunology*
  • Amyloidosis / pathology
  • Cells, Cultured
  • Chemotaxis / drug effects
  • Chemotaxis / immunology
  • Chronic Disease
  • Female
  • Glycation End Products, Advanced / pharmacology
  • Humans
  • Interleukin 1 Receptor Antagonist Protein
  • Kidney Failure, Chronic / immunology
  • Kidney Failure, Chronic / pathology*
  • Kidney Failure, Chronic / therapy
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Middle Aged
  • Monocytes / cytology
  • Monocytes / immunology
  • Monocytes / pathology
  • Receptors, Transforming Growth Factor beta / analysis
  • Renal Dialysis / adverse effects*
  • Sialoglycoproteins / analysis
  • Sialoglycoproteins / metabolism
  • Synovial Membrane / chemistry
  • Synovial Membrane / immunology
  • Synovial Membrane / pathology
  • Transforming Growth Factor beta / analysis
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / immunology*
  • Tumor Necrosis Factor-alpha / analysis
  • Tumor Necrosis Factor-alpha / metabolism
  • beta 2-Microglobulin / pharmacology


  • Glycation End Products, Advanced
  • IL1RN protein, human
  • Interleukin 1 Receptor Antagonist Protein
  • Receptors, Transforming Growth Factor beta
  • Sialoglycoproteins
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • beta 2-Microglobulin