Transforming growth factor-beta is involved in the pathogenesis of dialysis-related amyloidosis.
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.
Matsuo
K
K
Department of Medicine, Division of Nephrology, Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232-2372, USA.
Ikizler
T A
TA
Hoover
R L
RL
Nakamoto
M
M
Yasunaga
C
C
Pupim
L B
LB
Hakim
R M
RM
D000368:Aged; D000686:Amyloidosis / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D002908:Chronic Disease; D005260:Female; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007676:Kidney Failure, Chronic / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000473:pathology; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D006435:Renal Dialysis / Q000009:adverse effects*; D012795:Sialoglycoproteins / Q000032:analysis / Q000378:metabolism; D013583:Synovial Membrane / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000494:pharmacology
D017127:Glycation End Products, Advanced; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D018125:Receptors, Transforming Growth Factor beta; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D001613:beta 2-Microglobulin