title: Bicyclol promotes toll-like 2 receptor recruiting inosine 5'-monophosphate dehydrogenase II to exert its anti-inflammatory effect.
abstract: The aim was to investigate potential targets and anti-inflammatory mechanisms of bicyclol, which has been extensively used in clinic for decades in China. Tar-Fis-Dock, virtual molecular docking system, showed that inosine 5'-monophosphate dehydrogenase II (IMPDH II) has the highest probability of binding to bicyclol. To investigate the possible role of IMPDH II in mechanisms of bicyclol, recombinant enzyme models, mice splenic lymphocytes, and human lymphocytes were used. Bicyclol (1-5 μM) significantly inhibited the proliferation of mice splenic lymphocytes stimulated by concanavalin A (conA). However, bicyclol did not show inhibitory effects on proliferation of human peripheral blood mononuclear cells (hPBMC) induced by phytohemagglutinin (PHA). IMPDH II enzyme kinetic model showed that bicyclol only had a slight regulatory effect on IMPDH II enzyme activity. These results revealed that bicyclol may be not a conventional inhibitor of IMPDH II. Further studies showed that bicyclol could promote recruitment of IMPDH II by active toll-like 2 receptor (TLR2) complex. Such effects lead to the reduction of nuclear factor κB (NF-κB) expression, increase in I-κB expression, and decrease in cytokine release, including tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). It may be a new mechanism of bicyclol for its anti-inflammatory effect.
authors.affiliation: a State Key Laboratory of Bioactive Substance and Function of Natural Medicines , Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , China.
authors.forename: You-Wen
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: a State Key Laboratory of Bioactive Substance and Function of Natural Medicines , Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , China.
authors.forename: Yan-Shen
authors.initials: YS
authors.lastname: Guo
authors.affiliation: a State Key Laboratory of Bioactive Substance and Function of Natural Medicines , Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , China.
authors.forename: Xiu-Qi
authors.initials: XQ
authors.lastname: Bao
authors.affiliation: a State Key Laboratory of Bioactive Substance and Function of Natural Medicines , Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , China.
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.affiliation: a State Key Laboratory of Bioactive Substance and Function of Natural Medicines , Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001713:Biphenyl Compounds; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C477843:bicyclol; D007168:IMP Dehydrogenase
keywords: Bicyclol; IMPDH II; NF-κB; TLR2; lymphocytes