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

Abstract

Background. Advanced glycation end product-modified β2-microglobulin (AGE-β2m) 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-β (TGF-β) 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-β in the pathogenesis of DRA. Methods. We performed an immunohistochemical study of DRA tissues (8 cases) to confirm the existence of TGF-βs and their receptors; we also performed a chemotaxis assay of human monocytes as well as enzyme-linked immunosorbent assay (ELISA) of TGF-β1, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-1 receptor antagonist (IL-1Ra) in the supernatant of human monocyte-derived macrophage cell culture under varying conditions of incubation with TGF-β1, AGE-β2m, and TGF-β1 antibody additions. Results. There was positive staining for TGF-βs (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-β2m also induced TGF-β1 production by macrophages in a dose-dependent manner (410 ± 80 pg/mL at 12.5 μg/mL, 621 ± 62 pg/mL at 25 μg/mL, and 776 ± 62 pg/mL at 50 μg/mL of AGE-β2m). AGE-β2m induced significant TNF-α and IL-1Ra production by macrophage. The addition of exogenous TGF-β1 (0.1 to 10 ng/mL) decreased AGE-β2m-induced TNF-α production and increased IL-1Ra production in a dose-dependent fashion. IL-1β production was not effected by any experimental conditions. In chemotaxis assay, anti-TGF-β1 antibody (0.1 to 10 μg/mL) attenuated AGE-β2m-induced monocyte chemotaxis. Conclusions. These results provide the first evidence to our knowledge for the presence of TGF-β in DRA tissue, as well as the stimulatory action of AGE-β2m on tissue macrophages. In turn, TGF-β suppresses the proinflammatory activation of macrophages, suggesting a dual role for TGF-β in the inflammatory process of DRA. These observations may provide a pathophysiologic link between TGF-β and DRA.