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

被引:190
作者
Xu, Tao [1 ]
Wang, Xiaohu [2 ,3 ]
Zhong, Bo [2 ,3 ]
Nurieva, Roza I. [2 ,3 ]
Ding, Sheng [1 ]
Dong, Chen [2 ,3 ]
机构
[1] Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, Dept Pharmaceut Chem, San Francisco, CA 94158 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Ctr Inflammat & Canc, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
GROWTH-FACTOR-BETA; GAMMA-T; TH17; CELLS; DIFFERENTIATION; LINEAGE; ALPHA; EXPRESSION; DISTINCT;
D O I
10.1074/jbc.C111.250407
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 ROR gamma t. Here we show that ursolic acid (UA), a small molecule present in herbal medicine, selectively and effectively inhibits the function of ROR gamma t, 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.
引用
收藏
页码:22707 / 22710
页数:4
相关论文
共 23 条
[1]   TH 17 cells in development:: an updated view of their molecular identity and genetic programming [J].
Dong, Chen .
NATURE REVIEWS IMMUNOLOGY, 2008, 8 (05) :337-348
[2]   Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages [J].
Harrington, LE ;
Hatton, RD ;
Mangan, PR ;
Turner, H ;
Murphy, TL ;
Murphy, KM ;
Weaver, CT .
NATURE IMMUNOLOGY, 2005, 6 (11) :1123-1132
[3]   Ursolic Acid Inhibits IL-1β or TNF-α-Induced C6 Glioma Invasion Through Suppressing the Association ZIP/p62 With PKC-ζ and Downregulating the MMP-9 Expression [J].
Huang, Hsiu-Chen ;
Huang, Chien-Yu ;
Lin-Shiau, Shoei-Yn ;
Lin, Jen-Kun .
MOLECULAR CARCINOGENESIS, 2009, 48 (06) :517-531
[4]   Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis [J].
Hueber, Wolfgang ;
Patel, Dhavalkumar D. ;
Dryja, Thaddeus ;
Wright, Andrew M. ;
Koroleva, Irina ;
Bruin, Gerard ;
Antoni, Christian ;
Draelos, Zoe ;
Gold, Michael H. ;
Durez, Patrick ;
Tak, Paul P. ;
Gomez-Reino, Juan J. ;
Foster, C. Stephen ;
Kim, Rosa Y. ;
Samson, C. Michael ;
Falk, Naomi S. ;
Chu, David S. ;
Callanan, David ;
Quan Dong Nguyen ;
Rose, Kristine ;
Haider, Asifa ;
Di Padova, Franco .
SCIENCE TRANSLATIONAL MEDICINE, 2010, 2 (52)
[5]   Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity [J].
Huh, Jun R. ;
Leung, Monica W. L. ;
Huang, Pengxiang ;
Ryan, Daniel A. ;
Krout, Michael R. ;
Malapaka, Raghu R. V. ;
Chow, Jonathan ;
Manel, Nicolas ;
Ciofani, Maria ;
Kim, Sangwon V. ;
Cuesta, Adolfo ;
Santori, Fabio R. ;
Lafaille, Juan J. ;
Xu, H. Eric ;
Gin, David Y. ;
Rastinejad, Fraydoon ;
Littman, Dan R. .
NATURE, 2011, 472 (7344) :486-490
[6]   Ursolic acid: An anti- and pro-inflammatory, triterpenoid [J].
Ikeda, Yasutaka ;
Murakami, Akira ;
Ohigashi, Hajime .
MOLECULAR NUTRITION & FOOD RESEARCH, 2008, 52 (01) :26-42
[7]   The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells [J].
Ivanov, Ivaylo I. ;
McKenzie, Brent S. ;
Zhou, Liang ;
Tadokoro, Carlos E. ;
Lepelley, Alice ;
Lafaille, Juan J. ;
Cua, Daniel J. ;
Littman, Dan R. .
CELL, 2006, 126 (06) :1121-1133
[8]   Structural Basis for Hydroxycholesterols as Natural Ligands of Orphan Nuclear Receptor RORγ [J].
Jin, Lihua ;
Martynowski, Dariusz ;
Zheng, Songyang ;
Wada, Taira ;
Xie, Wen ;
Li, Yong .
MOLECULAR ENDOCRINOLOGY, 2010, 24 (05) :923-929
[9]   IL-17 and Th17 Cells [J].
Korn, Thomas ;
Bettelli, Estelle ;
Oukka, Mohamed ;
Kuchroo, Vijay K. .
ANNUAL REVIEW OF IMMUNOLOGY, 2009, 27 :485-517
[10]  
Lauthier F, 2000, ANTI-CANCER DRUG, V11, P737