title: Norisoboldine inhibits the production of interleukin-6 in fibroblast-like synoviocytes from adjuvant arthritis rats through PKC/MAPK/NF-κB-p65/CREB pathways.
abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine secreted by macrophages and others and it has been proven to be a potential therapeutic target of RA. Norisoboldine (NOR) is the main isoquinoline alkaloid constituent in the dry roots of Lindera aggregata (Sims) Kosterm. (L. strychnifolia Vill.), which has long been used in traditional Chinese medicine for treating RA and other diseases. Our previous studies indicated that NOR was able to attenuate inflammation and joint destruction in collagen II-induced arthritis of mice. To further recognize the anti-rheumatoid potentials of NOR, the present study addressed whether and how NOR interfered with IL-6 production from fibroblast-like synoviocytes (FLS), key effector cells in the development and progression of RA. FLS, obtained from the synovial tissues of rats with adjuvant arthritis, showed incremental release of IL-6 after stimulated with IL-1β in vitro. NOR (10, 30, and 60 µM) could reduce the production of IL-6 in a concentration-dependent manner. It also down-regulated the phosphorylations of mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), and transcriptional factor nuclear factor-κB (NF-κB)-p65 (ser 276) as well as cAMP response element-binding protein (CREB) in FLS. By using specific inhibitors, PKC was shown to be the upstream protein of MAPKs, and p38 MAPK was at the upstream of CREB. It was concluded that preventing IL-6 release from FLS might be an important mechanism for NOR displaying anti-RA property, and the action of NOR was relative to inhibition of PKC/MAPKs/p65/CREB pathways.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Wei
authors.forename: Fengyun
authors.initials: F
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.forename: Qian
authors.initials: Q
authors.lastname: Lu
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xia
authors.forename: Guixin
authors.initials: G
authors.lastname: Chou
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000166:cytology*
chemical_list: D000470:Alkaloids; D017362:Cyclic AMP Response Element-Binding Protein; D015850:Interleukin-6; D016328:NF-kappa B; C464745:norisoboldine; D011493:Protein Kinase C