Protein geranylgeranylation regulates the balance between Th17 cells and Foxp3+ regulatory T cells

Abstract

Recent studies have suggested that statins, the inhibitors for 3-hydroxy-3-methyglutaryl (HMG)-CoA reductase in the mevalonate pathway, exhibit anti-inflammatory effects. However, the immune modulatory effects of statins on the differentiation of CD4(+) T cells and their underlying mechanisms are still largely unknown. To address these issues, we examined the effect of simvastatin and inhibitors for protein farnesylation and geranylgeranylation on the differentiation of IL-17-producing T cells (T(h)17 cells) and Foxp3(+) CD4(+) T cells. Simvastatin inhibited the differentiation of T(h)17 cells through the inhibition of HMG-CoA reductase activity but enhanced the differentiation of Foxp3(+) CD4(+) T cells. Geranylgeranyltransferase I inhibitor, GGTI-298, but not farnesyltransferase inhibitor, FTI-277, mimicked the effects of simvastatin, indicating that the inhibition of protein geranylgeranylation is responsible for the effects. Moreover, Foxp3(+) CD4(+) T cells developed in the presence of transforming growth factor-beta and GGTI-298 functioned as regulatory T cells (Tregs) in in vitro T cell proliferation assay as well as in an autoimmune colitis model. Finally, GGTI-298 induced SOCS3 expression and inhibited IL-6-induced signal transducers and activators of transcription3 phosphorylation in CD4(+) T cells. Taken together, these results indicate that protein geranylgeranylation enhances the differentiation of T(h)17 cells and inhibits the differentiation of Foxp3(+) Tregs partly via the inhibition of SOCS3 expression.

Farnesyltransferase Inhibitor FTI-277 Reduces Mortality of Septic Mice along with Improved Bacterial Clearance

“…This result seems to be different from previous findings that statins promotes in vitro differentiation of Foxp3 ϩ Tregs from CD4 ϩ T cells (Mausner-Fainberg et al, 2008;Kagami et al, 2009). It is noteworthy that a previous study has shown that simvastatin and geranylgeranyltransferase inhibitor, but not FTI-277, promotes differentiation of Foxp3 ϩ Tregs from CD4 ϩ T cells in vitro (Kagami et al, 2009). Therefore, it is tempting to speculate that inhibition of farnesylation rather than geranylgeranylation may play an important role in the immunostimulatory actions of statins in septic mice.…”

Stabilization of high-risk plaques

“…On the other hand, there was no change in the anti-inflammatory cytokines that are related to Th 2 (IL-4 and IL-10) (211). It has been reported that statins promote the differentiation of Tregs (212), and restrain the differentiation of Th 17 (213). Kruppel-like factor 2 (KLF2), which regulates the expression of molecules essential for naive T cell recirculation and the maintenance of T cell quiescence, plays a key role in this mechanism (214).…”

Immunomodulatory synergy by combining atorvastatin and rapamycin in the treatment of experimental autoimmune encephalomyelitis (EAE)

“…This indicates that the beneficial immunomodulatory effects of statins may involve both APC and T cell functions (Youssef et al, 2002;Aktas et al, 2003). Other studies report that statins enhance differentiation of Foxp3+ Tregs and inhibit differentiation of Th17 cells in vitro (Kagami et al, 2009).…”