Protein geranylgeranylation regulates the balance between Th17 cells and Foxp3+ regulatory T cells.
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.
Kagami
Shin-ichiro
S
Department of Molecular Genetics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, Japan.
Owada
Takayoshi
T
Kanari
Hiroko
H
Saito
Yukari
Y
Suto
Akira
A
Ikeda
Kei
K
Hirose
Koichi
K
Watanabe
Norihiko
N
Iwamoto
Itsuo
I
Nakajima
Hiroshi
H
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D054876:Prenylation / Q000187:drug effects / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D016511:Severe Combined Immunodeficiency; D019821:Simvastatin / Q000494:pharmacology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D001549:Benzamides; C096856:FTI 277; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C102521:GGTI 298; D020381:Interleukin-17; D015850:Interleukin-6; C111390:OVA 323-339; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D010047:Ovalbumin; D008715:Methionine; D019821:Simvastatin