RT Journal Article SR Electronic T1 SH479, a Betulinic Acid Derivative, Ameliorates Experimental Autoimmune Encephalomyelitis by Regulating the T Helper 17/Regulatory T Cell Balance JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 464 OP 474 DO 10.1124/mol.116.107136 VO 91 IS 5 A1 Jing Li A1 Ji Jing A1 Yang Bai A1 Zhen Li A1 Roumei Xing A1 Binhe Tan A1 Xueyun Ma A1 Wen-Wei Qiu A1 Changsheng Du A1 Bing Du A1 Fan Yang A1 Jie Tang A1 Stefan Siwko A1 Mingyao Liu A1 Huaqing Chen A1 Jian Luo YR 2017 UL http://molpharm.aspetjournals.org/content/91/5/464.abstract AB CD4+ T helper cells, especially T helper 17 (TH17) cells, combined with immune regulatory network dysfunction, play key roles in autoimmune diseases including multiple sclerosis (MS). Betulinic acid (BA), a natural pentacyclic triterpenoid, has been reported to be involved in anti-inflammation, in particular having an inhibitory effect on proinflammatory cytokine interleukin 17 (IL-17) and interferon-γ (IFN-γ) production. In this study, we screened BA derivatives and found a BA derivative, SH479, that had a greater inhibitory effect on TH17 differentiation. Our further analysis showed that SH479 had a greater inhibitory effect on TH17 and TH1, and a more stimulatory effect on regulatory T (Treg) cells. To evaluate the effects of SH479 on autoimmune diseases in vivo, we employed the extensively used MS mouse model experimental autoimmune encephalomyelitis (EAE). Our results showed that SH479 ameliorated clinical and histologic signs of EAE in both prevention and therapeutic protocols by regulating the TH17/Treg balance. SH479 dose-dependently reduced splenic lymphocyte proinflammatory factors and increased anti-inflammatory factors. Moreover, SH479 specifically inhibited splenic lymphocyte viability from EAE mice but not normal splenic lymphocyte viability. At the molecular level, SH479 inhibited TH17 differentiation by regulating signal transducer and activator of transcription-3 (STAT3) phosphorylation, DNA binding activity, and recruitment to the Il-17a promoter in CD4+ T cells. Furthermore, SH479 promoted the STAT5 signaling pathway and inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Together, our data demonstrated that SH479 ameliorated EAE by regulating the TH17/Treg balance through inhibiting the STAT3 and NF-κB pathways while activating the STAT5 pathway, suggesting that SH479 is a potential novel drug candidate for autoimmune diseases including MS.