Globotriaosylceramide (Gb3) induces a proinflammatory cytokine profile in dendritic cells and macrophages: Consequences for Fabry disease

DE FRANCESCO P N; MUCCI J M; CECI R; ROZENFELD P A

Orlando, FL

Congreso; Lysosomal Disease Network's 9th Annual WORLD Symposium; 2013

Lysosomal Disease Network

Fabry disease (FD) is an X-linked genetic disorder characterized by the deficiency in the activity of the lysosomal enzyme alpha-galactosidase A (Gal), leading to the accumulation of globotriaosylceramide (Gb3). Previous results of our group showed increased expression and production of proinflammatory cytokines in peripheral blood mononuclear cells (PBMC) from patients with EF, in particular dendritic cells (DC) and monocytes (M). The aim of this study is to investigate the effects of Gb3 on the production of cytokines in DC and macrophages (M) derived from normal PBMC monocytes treated with DGJ, an inhibitor of Gal. PBMC were isolated from normal buffy coats, and M were purified and cultured in the presence of GM-CSF and IL-4, or M-CSF, to induce their differentiation into DC and M, respectively. Obtained cells were then cultured in the presence or absence of 20 μM Gb3 and/or 200 M DGJ and the levels of IL-beta, IL-6 and TNF were analyzed in the supernatants. Both cultures showed a significant increase in production of IL-1 and TNF , relative to the control, only in the case of alpha-galactosidase enzyme f combined Gb3 and DGJ treatment (DC p = 0.0018 and p = 0.0041, M p = 0.0002 and p = 0.0054, respectively). A similar trend was observed for IL-6. Moreover, addition of a TLR4-blocking antibody completely abolished the observed effect in M treated with Gb3 and DGJ. These results show that Gb3, possibly by interacting with TLR4, can induce a proinflammatory state, similar to that observed in PBMC from patients with FD, and could be directly involved in the pathogenesis of this disease.