title: Neurotropin suppresses inflammatory cytokine expression and cell death through suppression of NF-κB and JNK in hepatocytes.
abstract: Inflammatory response and cell death in hepatocytes are hallmarks of chronic liver disease, and, therefore, can be effective therapeutic targets. Neurotropin® (NTP) is a drug widely used in Japan and China to treat chronic pain. Although NTP has been demonstrated to suppress chronic pain through the descending pain inhibitory system, the action mechanism of NTP remains elusive. We hypothesize that NTP functions to suppress inflammatory pathways, thereby attenuating disease progression. In the present study, we investigated whether NTP suppresses inflammatory signaling and cell death pathways induced by interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) in hepatocytes. NTP suppressed nuclear factor-κB (NF-κB) activation induced by IL-1β and TNFα assessed by using hepatocytes isolated from NF-κB-green fluorescent protein (GFP) reporter mice and an NF-κB-luciferase reporter system. The expression of NF-κB target genes, Il6, Nos2, Cxcl1, ccl5 and Cxcl2 induced by IL-1β and TNFα was suppressed after NTP treatment. We also found that NTP suppressed the JNK phosphorylation induced by IL-1β and TNFα. Because JNK activation contributes to hepatocyte death, we determined that NTP treatment suppressed hepatocyte death induced by IL-1β and TNFα in combination with actinomycin D. Taken together, our data demonstrate that NTP attenuates IL-1β and TNFα-mediated inflammatory cytokine expression and cell death in hepatocytes through the suppression of NF-κB and JNK. The results from the present study suggest that NTP may become a preventive or therapeutic strategy for alcoholic and non-alcoholic fatty liver disease in which NF-κB and JNK are thought to take part.
authors.affiliation: Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Bi
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Roh
authors.affiliation: Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmacological Research, Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Company Ltd., Kato, Hyogo, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Naiki
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Koichi
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California, United States of America; Department of Surgery, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011134:Polysaccharides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D016328:NF-kappa B; D011134:Polysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D003609:Dactinomycin; C010491:neurotropin; D048031:JNK Mitogen-Activated Protein Kinases