title: Hepatic stellate cells relay inflammation signaling from sinusoids to parenchyma in mouse models of immune-mediated hepatitis.
abstract: Hepatic stellate cells (HSCs) constitute the liver sinusoid with Kupffer cells and liver sinusoidal endothelial cells. While the sinusoid functions as the gateway to liver inflammation, whether HSCs contribute to liver inflammation and, if so, how they exert such functions remain elusive. Here, we found that mouse as well as human HSCs expressed DP1 receptor for prostaglandin D2 selectively in the liver. Pharmacological stimulation of DP1 by BW245C, a DP1-selective agonist, suppressed the activation of cultured HSCs by tumor necrosis factor-α at least in part through down-regulation of nuclear factor kappa-light-chain-enhancer of activated B cells signaling and inhibition of c-Jun N-terminal kinase phosphorylation. DP1 deficiency or BW245C administration in mice significantly enhanced or suppressed concanavalin A (ConA)-induced hepatitis, respectively. ConA injection induced tumor necrosis factor-α and interferon-γ expression in the sinusoid, which was suppressed by administration of BW245C. Coculture of spleen cells and liver nonparenchymal cells showed that ConA first activated spleen cells and that this activation led to activation of nonparenchymal cells to secondarily produce tumor necrosis factor-α and interferon-γ. Microarray analysis revealed ConA-induced expression of endothelin-1, tissue factor, and chemokines in the liver and inducible nitric oxide synthase in hepatocytes, resulting in flow stagnation, leukocyte adherence and migration to the parenchyma, and hepatocyte death. DP1 stimulation inhibits all these events in the liver. Therefore, HSCs mediate amplification of ConA-induced liver inflammation in the sinusoid, causing direct and indirect hepatocyte injury, and DP1 stimulation inhibits this HSC activation.
  
  
  CONCLUSIONS
  HSCs integrate cytokine-mediated inflammatory responses in the sinusoids and relay them to the liver parenchyma, and these HSC actions are inhibited by DP1 stimulation.
authors.affiliation: Department of Pharmacology, Kyoto University, Kyoto, Japan.|Center for Innovation in Immunoregulatory Technology and Therapeutics, Kyoto University, Kyoto, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Pharmacology, Kyoto University, Kyoto, Japan.|Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Kitipong
authors.initials: K
authors.lastname: Soontrapa
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Target Therapy Oncology, Faculty of Medicine, Kyoto University, Kyoto, Japan.|Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.affiliation: Center for Innovation in Immunoregulatory Technology and Therapeutics, Kyoto University, Kyoto, Japan.
authors.forename: Catharina Sagita
authors.initials: CS
authors.lastname: Moniaga
authors.affiliation: Center for Innovation in Immunoregulatory Technology and Therapeutics, Kyoto University, Kyoto, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
authors.affiliation: Department of Pharmacology, Kyoto University, Kyoto, Japan.|Center for Innovation in Immunoregulatory Technology and Therapeutics, Kyoto University, Kyoto, Japan.|Japan Science and Technology Corporation, Core Research for Evolutional Science and Technology, Tokyo, Japan.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D018925:Chemokines / Q000187:drug effects / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006526:Hepatitis C / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018925:Chemokines; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma