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Receptor-interacting protein kinase 3 mediates macrophage/monocyte activation in autoimmune hepatitis and regulates

Jun Zhang1, Liping Guo1, Mengjing Liu1

  • 1Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, People's Republic of China.

United European Gastroenterology Journal
|August 8, 2018
PubMed
Abstract

Insights

Receptor-interacting protein kinase 3 (RIP3) signaling drives macrophage activation and IL-6 production in autoimmune hepatitis (AIH). This pathway is a novel target for 6-thioguanine (6-TG) therapy in AIH.

Area of Science:

  • Immunology
  • Hepatology
  • Molecular Biology

Background:

  • The role of macrophages/monocytes in autoimmune hepatitis (AIH) pathogenesis is not fully understood.
  • Receptor-interacting protein kinase 3 (RIP3) is a key inflammatory signaling adapter.
  • This study investigates RIP3's involvement in macrophage/monocyte activation in AIH.

Purpose of the Study:

  • To elucidate the role of RIP3 in macrophage/monocyte activation in autoimmune hepatitis (AIH).
  • To explore the relationship between RIP3 signaling and inflammatory cytokine production in AIH.
  • To identify RIP3 as a potential therapeutic target for AIH.

Main Methods:

  • Analysis of liver tissues and monocytes from AIH patients using double-immunofluorescence and Western blotting.
  • In vitro studies using RAW264.7 macrophages to investigate RIP3 signaling pathways.
  • Assessment of cytokine expression changes upon RIP3 activation and inhibition.

Main Results:

  • Macrophages in AIH liver tissues predominantly expressed RIP3, correlating with serum hepatic enzyme levels.
  • RIP3 activation in macrophages upregulated pro-inflammatory cytokines (IL-1β, IL-6, IL-10) and downregulated anti-inflammatory cytokines (IL-4, TGF-β).
  • Necrostatin-1 and 6-thioguanine (6-TG) significantly reduced IL-6 production, with increased IL-6 gene expression observed in AIH liver tissues.

Conclusions:

  • RIP3 signaling is implicated in macrophage/monocyte activation in AIH.
  • RIP3 mediates IL-6 production, representing a novel molecular mechanism for 6-TG action.
  • Targeting RIP3 signaling presents a promising therapeutic strategy for autoimmune hepatitis.
Keywords:
Autoimmune hepatitisinterleukin-6macrophagesreceptor-interacting protein kinase 3

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