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Hepatic stellate cells relay inflammation signaling from sinusoids to parenchyma in mouse models of immune‐mediated hepatitis
Author(s) -
Fujita Tomoko,
Soontrapa Kitipong,
Ito Yoshiya,
Iwaisako Keiko,
Moniaga Catharina Sagita,
Asagiri Masataka,
Majima Masataka,
Narumiya Shuh
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28112
Subject(s) - hepatic stellate cell , sinusoid , liver cytology , inflammation , biology , tumor necrosis factor alpha , chemokine , hepatocyte , cytokine , prostaglandin d2 , cancer research , endocrinology , microbiology and biotechnology , immunology , prostaglandin , biochemistry , liver metabolism , in vitro
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 D 2 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. (H epatology 2016;63:1325–1339)