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A20 in hepatic stellate cells suppresses chronic hepatitis by inhibiting DCLK1-JNK pathway-dependent chemokines.
Watakabe, Keiya; Miyoshi, Masato; Kakinuma, Sei; Sato, Ayako; Tsuchiya, Jun; Shimizu, Taro; Mochida, Tomohiro; Inada, Kento; Kaneko, Shun; Kawai-Kitahata, Fukiko; Murakawa, Miyako; Nitta, Sayuri; Nakagawa, Mina; Oshima, Shigeru; Watanabe, Mamoru; Ma, Averil; Asahina, Yasuhiro; Okamoto, Ryuichi.
Afiliación
  • Watakabe K; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Miyoshi M; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Kakinuma S; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Sato A; Department of Clinical and Diagnostic Laboratory Science, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Tsuchiya J; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Shimizu T; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Mochida T; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Inada K; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Kaneko S; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Kawai-Kitahata F; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Murakawa M; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Nitta S; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Nakagawa M; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Oshima S; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Watanabe M; Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Ma A; Faculty of Medicine, Juntendo University, Tokyo, Japan.
  • Asahina Y; Department of Medicine, University of California San Francisco, San Francisco, California, USA.
  • Okamoto R; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
FASEB J ; 38(13): e23757, 2024 Jul 15.
Article en En | MEDLINE | ID: mdl-38965999
ABSTRACT
Hepatic stellate cells (HSCs) are responsible for liver fibrosis accompanied by its activation into myofibroblasts and the abundant production of extracellular matrix. However, the HSC contribution to progression of liver inflammation has been less known. We aimed to elucidate the mechanism in HSCs underlying the inflammatory response and the function of tumor necrosis factor α-related protein A20 (TNFAIP3). We established A20 conditional knockout (KO) mice crossing Twist2-Cre and A20 floxed mice. Using these mice, the effect of A20 was analyzed in mouse liver and HSCs. The human HSC line LX-2 was also used to examine the role and underlying molecular mechanism of A20. In this KO model, A20 was deficient in >80% of HSCs. Spontaneous inflammation with mild fibrosis was found in the liver of the mouse model without any exogenous agents, suggesting that A20 in HSCs suppresses chronic hepatitis. Comprehensive RNA sequence analysis revealed that A20-deficient HSCs exhibited an inflammatory phenotype and abnormally expressed chemokines. A20 suppressed JNK pathway activation in HSCs. Loss of A20 function in LX-2 cells also induced excessive chemokine expression, mimicking A20-deficient HSCs. A20 overexpression suppressed chemokine expression in LX-2. In addition, we identified DCLK1 in the genes regulated by A20. DCLK1 activated the JNK pathway and upregulates chemokine expression. DCLK1 inhibition significantly decreased chemokine induction by A20-silencing, suggesting that A20 controlled chemokine expression in HSCs via the DCLK1-JNK pathway. In conclusion, A20 suppresses chemokine induction dependent on the DCLK1-JNK signaling pathway. These findings demonstrate the therapeutic potential of A20 and the DCLK1-JNK pathway for the regulation of inflammation in chronic hepatitis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Ratones Noqueados / Quimiocinas / Sistema de Señalización de MAP Quinasas / Células Estrelladas Hepáticas / Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa Límite: Animals / Humans / Male Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Ratones Noqueados / Quimiocinas / Sistema de Señalización de MAP Quinasas / Células Estrelladas Hepáticas / Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa Límite: Animals / Humans / Male Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos