期刊
FRONTIERS IN IMMUNOLOGY
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2017.00679
关键词
guanabenz; lipopolysaccharide-induced liver damage; TLR4; unfolded protein response; Ppp1r15a
类别
资金
- Innate Immunocytes in Health and Disease collaborative project
- l'Agence Nationale de la Recherche (ANR) [ANR-12-BSV2-0025-01, ANR-FCT 12-ISV3-0002-01]
- INFORM Labex [ANR-11-LABX-0054]
- DCBIOL Labex [ANR-11-LABEX-0043, ANR-10-IDEX-0001-02 PSL]
- A*MIDEX project - Excellence Initiative of Aix-Marseille University-A*MIDEX, a French Investissements d'Avenir program [ANR-11-IDEX-0001-02]
- Ilidio Pinho foundation
- PACA Region
- INSERM
- France Bio Imaging and the ImagImm CIML imaging core facility [ANR-10-INBS-04-01]
- [DEQ20140329536]
- Agence Nationale de la Recherche (ANR) [ANR-12-BSV2-0025] Funding Source: Agence Nationale de la Recherche (ANR)
Multi-organ failure in response to uncontrolled microbial infection is characterized by low blood pressure accompanied by a systemic over-inflammation state, caused by massive pro-inflammatory cytokines release and liver damage. Recently, the integrated stress response (ISR), characterized by eukaryotic translation initiation factor 2 alpha (eIF2 alpha) phosphorylation, was involved with controlling apoptosis in stressed hepatocytes and associated with poor survival to endotoxin challenge. Lipopolysaccharide (LPS) alone is able to induce the ISR in hepatocytes and can trigger massive liver damage along with tumor necrosis factor-alpha (TNF-alpha) expression. Consequently, drugs interfering with eIF2 alpha phosphorylation may represent potential candidates for the treatment of such pathologies. We, therefore, used Guanabenz (GBZ), a small compound with enhancing eIF2 alpha phosphorylation activity to evaluate its effect on bacterial LPS sensing and endotoxemia. GBZ is confirmed here to have an anti-inflammatory activity by increasing in vitro interleukin-10 (IL-10) production by LPS-stimulated dendritic cells. We further show that in the D-galactosamine (D-galN)/LPS-dependent lethality model, intraperitoneal injection of GBZ promoted mice survival, prevented liver damage, increased IL-10 levels, and inhibited TNF-alpha production. GBZ and its derivatives could therefore represent an interesting pharmacological solution to control systemic inflammation and associated acute liver failure.
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