Shifting the balance: expression of transforming growth factor β receptor subunit genes in relapsing-remitting multiple sclerosis patients treated with dimethyl fumarate.

In multiple sclerosis several alterations in transforming growth factor β (TGF-β) signaling in immune cells have been observed, however, little is known about gene expression of TGF-β receptor subunits. Dimethyl fumarate is a disease modifying drug that is still used to treat relapsing-remitting multiple sclerosis. Although its inhibitory effect on TGF-β signaling associated with SMAD proteins has been observed, its effect on the expression of TGF-β receptors is unknown. Expression of genes for TGF-β receptor subunits - TGFBR1, TGFBR2, as well as the co-receptor - TGFBR3 has been examined in blood from patients with relapsing-remitting multiple sclerosis, untreated and treated with dimethyl fumarate, as well as in healthy controls, using droplet digital PCR. TGF-β1 concentrations were determined in sera, using ELISA. Untreated patients had significantly lower TGFBR3 gene expression in blood than healthy controls (p<0.0001) and significantly lower serum concentration of TGF-β1 (p=0.0268), than healthy controls. Patients treated with dimethyl fumarate had significantly lower TGFBR2 and TGFBR1 gene expression (p=0.0054 and 0.0225 respectively) and significantly higher TGF-β1 (p=0.0113) serum concentrations than untreated patients. The percentage of T cells in blood of untreated relapsing-remitting multiple sclerosis (RRMS) patients was significantly higher than in healthy controls (p=0.0054), but in dimethyl fumarate-treated patients was not significantly different from the values in the other groups. Downregulation of the TGFBR3 gene and lower TGF-β1 serum concentration in relapsing-remitting multiple sclerosis can indicate a defective regulatory immune response. Downregulation of TGFBR1 and TGFBR2 genes could be one of the mechanisms for dimethyl fumarate-induced inhibition of TGF-β signaling.