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<title lang=en>The chemical inhibitors of cellular death, PJ34 and Necrostatin-1, down-regulate IL-33 expression in liver.</title>
<creator>Arshad, Muhammad Imran</creator>
<creator>Piquet-Pellorce, Claire</creator>
<creator>Filliol, Aveline</creator>
<creator>L'Helgoualc'H, Annie</creator>
<creator>Lucas-Clerc, Catherine</creator>
<creator>Jouan-Lanhouet, Sandrine</creator>
<creator>Dimanche-Boitrel, Marie-Thérèse</creator>
<creator>Samson, Michel</creator>
<contributor>Institut de recherche, santé, environnement et travail [Rennes] (Irset) ; Université d'Angers (UA) - Université des Antilles et de la Guyane (UAG) - Université de Rennes 1 (UR1) - École des Hautes Études en Santé Publique [EHESP] (EHESP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )</contributor>
<contributor>Laboratoire de biochimie générale ; Hôpital Pontchaillou - CHU Pontchaillou [Rennes]</contributor>
<description>International audience</description>
<source>ISSN: 0946-2716</source>
<source>EISSN: 1432-1440</source>
<source>Journal of Molecular Medicine</source>
<publisher>Springer Verlag</publisher>
<identifier>hal-01134319</identifier>
<identifier>https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134319</identifier>
<source>https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134319</source>
<source>Journal of Molecular Medicine, Springer Verlag, 2015, 93 (8), pp.867-878. 〈10.1007/s00109-015-1270-6〉</source>
<identifier>DOI : 10.1007/s00109-015-1270-6</identifier>
<relation>info:eu-repo/semantics/altIdentifier/doi/10.1007/s00109-015-1270-6</relation>
<identifier>PUBMED : 25747661</identifier>
<relation>info:eu-repo/semantics/altIdentifier/pmid/25747661</relation>
<language>en</language>
<subject lang=en>Cytokine Acute hepatitis RIP kinase PARP-1 IL-33 Fibroblasts</subject>
<subject>[SDV] Life Sciences [q-bio]</subject>
<type>info:eu-repo/semantics/article</type>
<type>Journal articles</type>
<description lang=en>Interleukin-33 (IL-33), a cytokine belonging to the IL-1 family, is crucially involved in inflammatory pathologies including liver injury and linked to various modes of cell death. However, a link between IL-33 and necroptosis or programmed necrosis in liver pathology remains elusive. We aimed to investigate the regulation of IL-33 during necroptosis-associated liver injury. The possible regulation of IL-33 during liver injury by receptor-interacting protein kinase 1 (RIPK1) and poly(ADP-ribose) polymerase 1 (PARP-1) was investigated in mice in vivo and in hepatic stellate cells in vitro. The liver immunohistopathology, flow cytometry, serum transaminase measurement, ELISA, and qPCR-based cytokine measurement were carried out. By using a chemical approach, we showed that pretreatment of mice with Necrostatin-1 (Nec-1) (inhibitor of RIPK1) and/or PJ34 (inhibitor of PARP-1) significantly protected mice against concanavalin A (ConA) liver injury (aspartate amino-transferase (AST)/alanine amino-transferase (ALT)) associated with down-regulated hepatocyte-specific IL-33 expression. In contrast, the expression level of most systemic cytokines (except for IL-6) or activation of liver immune cells was not altered by chemical inhibitors rather an increased infiltration of neutrophils in the liver. During polyinosine-polycytidylic acid (Poly(I:C))-induced acute hepatitis, liver injury and hepatocyte-specific IL-33 expression was also inhibited by PJ34 without any protective effect of PJ34 in CCl4-induced liver injury. Moreover, PJ34 down-regulated the protein expression of IL-33 in activated hepatic stellate cells by cocktail of cytokines or staurosporine in vitro. In conclusion, we evidenced that the Nec-1/PJ34 is a potent inhibitor of liver injury and Nec-1/PJ34 down-regulated hepatocyte-specific IL-33 expression in the liver in vivo or in hepatic stellate cells in vitro, suggesting IL-33 as a possible readout of necroptosis-involved liver pathologies. Necroptosis inhibitors can protect mice against liver injury induced by ConA or Poly(I:C). IL-33 expression in liver injury in vivo is inhibited by PJ34. IL-33 expression in hepatic stellate cells in vitro is inhibited by PJ34. Hepatocyte-specific IL-33 expression is down-regulated by Nec-1/PJ34 during hepatitis. IL-33 is a new marker of necroptosis-associated liver injuries.</description>
<date>2015-03-08</date>
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