The Natural Compound Notopterol Binds and Targets JAK2/3 to Ameliorate Inflammation and Arthritis

Cell Rep. 2020 Sep 15;32(11):108158. doi: 10.1016/j.celrep.2020.108158.

Authors

Qiong Wang¹, Xin Zhou², Long Yang³, Yongjian Zhao⁴, Zhihuan Chew⁵, Jun Xiao⁵, Chang Liu², Xin Zheng⁵, Yuxiao Zheng⁵, Qi Shi⁴, Qianqian Liang⁶, Yongjun Wang⁷, Hongyan Wang⁸

Affiliations

¹ Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
² State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Cancer Center, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai 200072, China.
³ Department of Rehabilitation Medicine, Shanghai Eighth People's Hospital, Shanghai 200235, China.
⁴ Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
⁵ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁶ Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: liangqianqiantcm@126.com.
⁷ Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: yjwang8888@126.com.
⁸ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: hongyanwang@sibcb.ac.cn.

PMID: 32937124
DOI: 10.1016/j.celrep.2020.108158

Abstract

The traditional Chinese medicinal herb Notopterygium incisum Ting ex H.T. Chang has anti-rheumatism activity, and a mass spectrometry assay of patients' serum after administration of the herb revealed that notopterol is the most abundant component enriched. However, the functions of notopterol and its molecular target in rheumatoid arthritis (RA) treatment remain unknown. Here, we show in different RA mouse strains that both oral and intraperitoneal administration of notopterol result in significant therapeutic effects. Mechanistically, notopterol directly binds Janus kinase (JAK)2 and JAK3 kinase domains to inhibit JAK/signal transducers and activators of transcription (JAK-STAT) activation, leading to reduced production of inflammatory cytokines and chemokines. Critically, combination therapy using both notopterol and tumor necrosis factor (TNF) blocker results in enhanced therapeutic effects compared to using TNF blocker alone. We demonstrate that notopterol ameliorates RA pathology by targeting JAK-STAT signaling, raising the possibility that notopterol could be effective in treating other diseases characterized by aberrant JAK-STAT signaling pathway.

Keywords: Collagen Induced Arthritis; LPS/IFNγ; Traditional Chinese Medicine; compound; macrophage.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arthritis, Experimental / drug therapy
Arthritis, Experimental / enzymology
Arthritis, Experimental / pathology
Arthritis, Experimental / prevention & control
Arthritis, Rheumatoid / drug therapy
Arthritis, Rheumatoid / enzymology
Arthritis, Rheumatoid / pathology*
Biological Products / administration & dosage
Biological Products / chemistry
Biological Products / pharmacology
Biological Products / therapeutic use
Chemokines / metabolism
Coumarins / administration & dosage
Coumarins / chemistry
Coumarins / pharmacology*
Coumarins / therapeutic use
Etanercept / pharmacology
Inflammation / drug therapy
Inflammation / enzymology
Inflammation / pathology*
Inflammation Mediators / metabolism
Interferon-gamma / pharmacology
Janus Kinase 2 / antagonists & inhibitors*
Janus Kinase 2 / chemistry
Janus Kinase 3 / antagonists & inhibitors*
Janus Kinase 3 / metabolism
Lipopolysaccharides
Macrophages / drug effects
Macrophages / metabolism
Mice, Inbred C57BL
Mice, Inbred DBA
Protein Domains
STAT Transcription Factors / metabolism
Tumor Necrosis Factor-alpha / pharmacology

Substances

Biological Products
Chemokines
Coumarins
Inflammation Mediators
Lipopolysaccharides
STAT Transcription Factors
Tumor Necrosis Factor-alpha
Interferon-gamma
notopterol
Janus Kinase 2
Janus Kinase 3
Etanercept