Natural Tregs (nTregs) develop in the thymus whereas induced regulatory T cells (iTregs) differentiate
in peripheral sites.1In vitro differentiation of iTregs is mediated by T-cell receptor (TCR) -mediated activation together with transforming growth factor-β (TGF-β) and interleukin-2 (IL-2).2 Both types of Tregs constitutively express Foxp3 [forkhead (FKH)-winged helix family protein of transcription regulators], which is the master gene mediating the immunosuppressive function of Tregs.3,4 It is likely that the induction of Foxp3 expression in Tregs Carfilzomib concentration with TGF-β is secondary to activation of the enhancer and promoter regions of the Foxp3 gene, as well as being secondary to regulation of histone
acetylation and DNA demethylation of the Foxp3 gene.5,6 The role of TGF-β in Treg induction in vivo is unclear because the optimal concentrations of TGF-β used to induce Foxp3 expression in vitro are unlikely to be present in vivo. Statins are widely used drugs for the treatment of hypercholesterolaemia. They function as competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is the rate-determining enzyme of the mevalonate pathway. More recent studies have also suggested that statins can mediate immunosuppressive functions and have proven effective in the treatment of autoimmune diseases or graft-versus-host disease in animal models.7–9 A number of mechanisms have been proposed to explain the immunosuppressive effects of the statins including inhibition of antigen presentation by inhibition of the induction of MHC class II expression, GSK3235025 research buy and blocking of T helper type 1 (Th1) cell differentiation by inhibiting
TCR-specific phosphorylation of Stat4 in Th1 differentiation.7,10 Suppression of Th1 differentiation Liothyronine Sodium by statins in the experimental autoimmune encephalomyelitis mouse model was mediated by inhibition of protein geranylgeranylation, one of the main downstream metabolic branches of the mevalonate pathway.10 Statins may also interfere with the interaction between T cells and antigen-presenting cells by inhibiting the functions of the β-integrin, lymphocyte function-associated antigen 1 (CD11a/CD18).11 Although direct effects of statins on Treg function have not been reported, a number of studies have suggested that Tregs play an important role in the control of pathology in atherosclerosis and atherosclerotic plaques have been reported to contain a lower percentage of Foxp3+ Tregs compared with normal tissue.12,13 Recently, a study has reported that the number of Foxp3+ T cells is elevated in the peripheral blood mononuclear cellsof patients who take statins.14 However, it is still unclear if statins directly increase the number of Foxp3+ cells or indirectly modulate the trafficking of Tregs into blood or to sites of immunopathology.