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The chemical inhibitors of cellular death, PJ34 and Necrostatin-1, down-regulate IL-33 expression in liver

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Abstract

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.

Key message

  • 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.

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Abbreviations

AST:

Aspartate amino-transferase

ALT:

Alanine amino-transferase

ConA:

Concanavalin A

IL-33:

Interleukin 33

IL-1RAcP:

Interleukin-1 receptor accessory protein

i.v.:

Intravenous

i.p.:

Intraperitoneal

Nec-1:

Necrostatin-1

PARP-1:

Poly(ADP-ribose) polymerase 1

P.I.:

Postinjection

RIPK:

Receptor-interacting protein kinase

Poly(I:C):

Polyinosine-polycytidylic acid

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Acknowledgments

This work was supported by INSERM, the Ministère de l’Education Nationale de la Recherche et de la Technologie, the University of Rennes 1, the Région Bretagne, the “Ligue contre le cancer, comités du grand Ouest”. Muhammad Imran Arshad was supported by a PhD fellowship from the Government of Pakistan and serving as an assistant professor under tenure track system (Higher Education Commission, University of Agriculture, Faisalabad). Sandrine Jouan-Lanhouet was supported by the Association pour la Recherche sur le Cancer (doctoral fellowship). For immunohistochemistry, cytometry analysis, and animal house facilities, we would like to thank the dedicated platforms (i.e., H2P2 (Pascale Bellaud and Roselyne Viel), cytometry platform (Dr. Gersende Lacombe), and animal house platforms (Laurence Touami) of SFR BIOSIT, University of Rennes 1, France.

Conflict of interest

The authors declare no financial or commercial conflict of interest.

Author information

Author notes

  1. Muhammad Imran Arshad

    Present address: Institute of Microbiology, University of Agriculture, Faisalabad, Pakistan

  2. Sandrine Jouan-Lanhouet

    Present address: Inflammation Research Center, Molecular Signaling and Cell Death Unit, VIB, Technologiepark 927, B-9052, Ghent, Belgium

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement and Travail (IRSET), 35043, Rennes, France

    Muhammad Imran Arshad, Claire Piquet-Pellorce, Aveline Filliol, Annie L’Helgoualc’h, Sandrine Jouan-Lanhouet, Marie-Thérèse Dimanche-Boitrel & Michel Samson

  2. Université de Rennes 1, 2, Avenue du Professeur Léon Bernard, 35043, Rennes Cedex, France

    Muhammad Imran Arshad, Claire Piquet-Pellorce, Aveline Filliol, Annie L’Helgoualc’h, Catherine Lucas-Clerc, Sandrine Jouan-Lanhouet, Marie-Thérèse Dimanche-Boitrel & Michel Samson

  3. Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, 35043, Rennes, France

    Muhammad Imran Arshad, Claire Piquet-Pellorce, Aveline Filliol, Annie L’Helgoualc’h, Sandrine Jouan-Lanhouet, Marie-Thérèse Dimanche-Boitrel & Michel Samson

  4. Service de Biochimie CHU Rennes, Université de Rennes 1, 35043, Rennes, France

    Catherine Lucas-Clerc

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Arshad, M.I., Piquet-Pellorce, C., Filliol, A. et al. The chemical inhibitors of cellular death, PJ34 and Necrostatin-1, down-regulate IL-33 expression in liver. J Mol Med 93, 867–878 (2015). https://doi.org/10.1007/s00109-015-1270-6

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