Ursolic Acid Suppresses Interleukin-17 (IL-17) Production by Selectively Antagonizing the Function of RORγt Protein

Chen Dong,Xiaohu Wang,Bo Zhong,Roza I. Nurieva,Tao Xu,Sheng Ding

doi:10.1074/jbc.c111.250407

Abstract

Th17 cells have recently emerged as a major player in inflammatory and autoimmune diseases via the production of pro-inflammatory cytokines IL-17, IL-17F, and IL-22. The differentiation of Th17 cells and the associated cytokine production is directly controlled by RORγt. Here we show that ursolic acid (UA), a small molecule present in herbal medicine, selectively and effectively inhibits the function of RORγt, resulting in greatly decreased IL-17 expression in both developing and differentiated Th17 cells. In addition, treatment with UA ameliorated experimental autoimmune encephalomyelitis. The results thus suggest UA as a valuable drug candidate or leading compound for developing treatments of Th17-mediated inflammatory diseases and cancer.

Highlights

Th17 cells have recently emerged as a major player in inflammatory and autoimmune diseases via the production of pro-inflammatory cytokines IL-17, IL-17F, and IL-22
Mice deficient in ROR␥ and those deficient in both ROR␥t and ROR␣ are defective in production of IL-17 and IL-17F and are resistant to experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis [7, 8]
ursolic acid (UA) did not alter the mRNA level of ROR␣, ROR␥t, RUNX1, and IRF4 in Th17 cells (Fig. 1 and data not shown), which are known to be important transcription regulators in Th17 cytokine expression [12]

Summary

Introduction

Th17 cells have recently emerged as a major player in inflammatory and autoimmune diseases via the production of pro-inflammatory cytokines IL-17, IL-17F, and IL-22. We show that ursolic acid (UA), a small molecule present in herbal medicine, selectively and effectively inhibits the function of ROR␥t, resulting in greatly decreased IL-17 expression in both developing and differentiated Th17 cells. To confirm our above result, we performed in vitro T cell differentiation using naive CD4ϩ cells in the presence of different amounts of UA and found that UA dose-dependently inhibited both human and mouse Th17 cell development and 2 ␮M UA inhibited Ͼ80% IL-17 expression in Th17 cells (Fig. 1).

Results

Conclusion