SH479, a Betulinic Acid Derivative, Ameliorates Experimental Autoimmune Encephalomyelitis by Regulating the T Helper 17/Regulatory T Cell Balance

Abstract

CD4 T helper cells, especially T helper 17 (T17) 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- (IFN-) production. In this study, we screened BA derivatives and found a BA derivative, SH479, that had a greater inhibitory effect on T17 differentiation. Our further analysis showed that SH479 had a greater inhibitory effect on T17 and T1, 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 T17/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 T17 differentiation by regulating signal transducer and activator of transcription-3 (STAT3) phosphorylation, DNA binding activity, and recruitment to the 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-B) signaling pathway. Together, our data demonstrated that SH479 ameliorated EAE by regulating the T17/Treg balance through inhibiting the STAT3 and NF-B pathways while activating the STAT5 pathway, suggesting that SH479 is a potential novel drug candidate for autoimmune diseases including MS.

The protective effect of betulinic acid on microvascular responsivity and protein expression in alzheimer disease induced by cerebral micro‐injection of beta‐amyloid and streptozotocin

“…For more explanation, in the context of dementia, the bypassing of Aβ oligomers possibly allows this triterpenoid to limit cell death susceptibility via inhibition of glial cell activation or ROS generation . The potent anti‐inflammatory function of BA (or its derivatives) also specifies its importance on immune‐dependent diseases such as lethal endotoxemia (or Autoimmune Encephalomyelitis) that trigger the levels of TNF‐alpha (increased trend) or IL‐10 (decreased trend) . Many papers are in accordance with the current data and clearly describe a significant increase in TNF‐alpha in the serum or hippocampi in dementia, while quantified IL‐10 levels only represent inconclusive data; although a high expression of hippocampal IL‐10 in AD transgenic mice could demonstrate a potent compensatory mechanism in the immune feedback .…”

“…15,40,41 The potent anti-inflammatory function of BA (or its derivatives) also specifies its importance on immune-dependent diseases such as lethal endotoxemia (or Autoimmune Encephalomyelitis) that trigger the levels of TNF-alpha (increased trend) or IL-10 (decreased trend). 42,43 Many papers are in accordance with the current data and clearly describe a significant increase in TNF-alpha in the serum or hippocampi in dementia, while quantified IL-10 levels only represent inconclusive data; although a high expression of hippocampal IL-10 in AD transgenic mice could demonstrate a potent compensatory mechanism in the immune feedback. 34,44,45 Restoring the cholinergic pool through inhibition of AchE and butyrylcholinesterase (BCHE) may provide another possible explanation for the protective effects of BA against AD.…”

Dual Targeting of Bile Acid Receptor-1 (TGR5) and Farnesoid X Receptor (FXR) Prevents Estrogen-Dependent Bone Loss in Mice

“…Our group's previous work demonstrated that SH‐479 could ameliorate experimental autoimmune encephalomyelitis (EAE) by promoting the STAT5 signaling pathway and suppressing NF‐κB signaling pathway . SH‐479 also inhibits collagen‐induced arthritis by modulating T‐cell JAK‐STAT pathways .…”

CD4+T cell specific B7-H1 selectively inhibits proliferation of naïve T cells and Th17 differentiation in experimental autoimmune encephalomyelitis

“…It had been provided substantial evidence that Th17 cells had significant role in MS. Up-regulation of Th17 cells and IL-17A was observerd in the CNS of MS patients, especially in chronic active lesions and acute lesions [ 16 , 17 ]. More importantly, inhibition of Th17 cell differentiation could significantly ameliorated MOG (35-55)-induced EAE [ 18 , 19 ]. For example, CD226 pAb administration was found to reduced onset of EAE by inhibiting Th1/Th17 production [ 20 ].…”