Journal of Ethnopharmacology 137 (2011) 457–468 Contents lists available at ScienceDirect Journal of Ethnopharmacology journa l h o me page: www.elsevier.com/locate/jethpharm Anti-inflammatory activities of Chinese herbal medicine sinomenine and Liang Miao San on tumor necrosis factor--activated human fibroblast-like synoviocytes in rheumatoid arthritis Da-Peng Chen a,b,1 , Chun-Kwok Wong a,c,d,∗,1 , Ping-Chung Leung c,d , Kwok-Pui Fung c,d,e , Clara Bik-San Lau c,d , Ching-Po Lau c,d , Edmund Kwok-Ming Li f , Lai-Shan Tam f , Christopher Wai-Kei Lam a,g,h a Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong b Department of Clinical Laboratory, Children’s Hospital of Chongqing Medical University, Chongqing, China c Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong d State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong e School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong f Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong g Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau h State Key Laboratory for Quality Research in Chinese Medicine, Macau a r t i c l e i n f o Article history: Received 20 December 2010 Received in revised form 9 May 2011 Accepted 10 May 2011 Available online 6 June 2011 Keywords: Cytokines Liang Miao San Rheumatoid arthritis Signal transduction Sinomenine Tumor necrosis factor- a b s t r a c t Aim of the study: Sinomenine, an alkaloid isolated from the root of Sinomenium acutum, has been used to alleviate the symptoms of rheumatic diseases. Liang Miao San (LMS), composed of the herbs Rhizoma Atractylodis (Cangzhu) and Cotex Phellodendri (Huangbai), is another traditional Chinese medicine formula for rheumatoid arthritis (RA) treatment. Although numerous studies have demonstrated the potential anti-inflammatory activities of sinomenine and LMS, the underlying intracellular mechanisms regulating the anti-inflammatory activities of sinomenine and LMS on human primary fibroblast-like synoviocytes (FLS) from RA patients and normal control subjects have not been elucidated. Materials and methods: We investigated the in vitro anti-inflammatory activity of sinomenine and LMS on inflammatory cytokine tumor necrosis factor (TNF)--mediated activation of human normal and RA-FLS. The underlying intracellular signaling molecules were analyzed quantitatively using flow cytometry. Results: Sinomenine was found to significantly inhibit TNF- induced cell surface expression of vascular cell adhesion molecule (VCAM)-1 and release of inflammatory cytokine and chemokine IL-6, CCL2 and CXCL8 from both normal and RA-FLS (all p < 0.05). Moreover, the suppression of sinomenine on TNF-  induced VCAM-1 expression and IL-6 release of RA-FLS was significantly higher than that of normal FLS (p < 0.05). LMS significantly inhibited TNF--induced inflammatory chemokines CXCL10 and CCL5 release from both normal and RA-FLS, with significantly higher suppression on CXCL10 secretion in RA-FLS than that of normal FLS (all p < 0.05). Further investigations showed that sinomenine and LMS could significantly suppress TNF--induced phosphorylation of inhibitor B and extracellular signal- regulated protein kinase, the central signaling molecules mediating TNF--induced VCAM-1 expression and chemokine production. Conclusion: Our results therefore provide a new insight into the differential anti-inflammatory activities of sinomenine and LMS through the suppression of TNF--activated FLS by modulating distinct intracellular signaling pathways in RA. © 2011 Elsevier Ireland Ltd. All rights reserved. ∗ Corresponding author at: Department of Chemical Pathology, The Chinese Uni- versity of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong. Tel.: +852 26322964; fax: +852 26365090. E-mail address: ck-wong@cuhk.edu.hk (C.-K. Wong). 1 These authors contributed equally to this work. 1. Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease, characterized by cytokine-mediated inflammation of the synovial lining of the joints and destruction of cartilage and bone (Wong et al., 2010). Fibroblast-like synoviocytes (FLS) are resident mes- enchymal cells of synovial joints and have been recognized to play an important role in the immunopathogenesis of RA. Synovial tissue 0378-8741/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2011.05.048