iNOS/NO is required for IRF1 activation in response to liver ischemia-reperfusion in mice

Du，Qiang1; Luo，Jing1,2; Yang，Mu Qing1,3; Liu，Quan1,4; Heres，Caroline1; Yan，Yi He1; Stolz，Donna5; Geller，David A.1

2020-06-09

10.1186/s10020-020-00182-2

MOLECULAR MEDICINE   影响因子和分区

1076-1551

1528-3658

BACKGROUND: Ischemia and reperfusion (I/R) induces cytokines, and up-regulates inducible nitric oxide synthase (iNOS), interferon regulatory factor-1(IRF1) and p53 up-regulated modulator of apoptosis (PUMA), which contribute to cell death and tissue injury. However, the mechanisms that I/R induces IRF1-PUMA through iNOS/NO is still unknown. METHODS: Ischemia was induced by occluding structures in the portal triad (hepatic artery, portal vein, and bile duct) to the left and median liver lobes for 60 min, and reperfusion was initiated by removal of the clamp. Induction of iNOS, IRF1 and PUMA in response to I/R were analyzed. I/R induced IRF1 and PUMA expression were compared between iNOS wild-type and iNOS knockout (KO) mice. Human iNOS gene transfected-cells were used to determine iNOS/NO signals targeting IRF1. To test whether HDAC2 was involved in the mediation of iNOS/NO-induced IRF1 transcriptional activities and its target gene (PUMA and p21) expression, NO donors were used in vitro and in vivo. RESULTS: IRF1 nuclear translocation and PUMA transcription elevation were markedly induced following I/R in the liver of iNOS wild-type mice compared with that in knock-out mice. Furthermore, I/R induced hepatic HDAC2 expression and activation, and decreased H3AcK9 expression in iNOS wild-type mice, but not in the knock-out mice. Mechanistically, over-expression of human iNOS gene increased IRF1 transcriptional activity and PUMA expression, while iNOS inhibitor L-NIL reversed these effects. Cytokine-induced PUMA through IRF1 was p53 dependent. IRF1 and p53 synergistically up-regulated PUMA expression. iNOS/NO-induced HDAC2 mediated histone H3 deacetylation and promoted IRF1 transcriptional activity. Moreover, treating the cells with romidepsin, an HDAC1/2 inhibitor decreased NO-induced IRF1 and PUMA expression. CONCLUSIONS: This study demonstrates a novel mechanism that iNOS/NO is required for IRF1/PUMA signaling through a positive-feedback loop between iNOS and IRF1, in which HDAC2-mediated histone modification is involved to up-regulate IRF1 in response to I/R in mice.

Histone deacetylase Inducible nitric oxide synthase Interferon regulatory factor-1 Ischemia-reperfusion Nitric oxide p53 up-regulated modulator of apoptosis

SCI

英语

其他

National Institutes of Health[HHSN276201200017C][P30DK120531-01]

Biochemistry & Molecular Biology ; Cell Biology ; Research & Experimental Medicine

Biochemistry & Molecular Biology ; Cell Biology ; Medicine, Research & Experimental

WOS:000541853500001

SPRINGER

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85086356384

Scopus

1.Thomas E. Starzl Transplant Institute,Department of Surgery,University of Pittsburgh,Kaufmann Medical Building,Pittsburgh,3471 Fifth AvenueSuite 300,15213,United States
2.Department of Surgery,Second Xiangya Hospital of Central South University,Changsha,139 Renmin Middle Road,410011,China
3.Department of Surgery,Shanghai Tenth People's Hospital,Tenth People's Hospital of Tongji University,301 Middle Yanchang Road,200072,China
4.Southern University of Science and Technology,School of Medicine,Shenzhen,1088 Xueyuan Blvd. ,Nanshan District,518055,China
5.Department of Cellular Biology,University of Pittsburgh,Pittsburgh,15213,United States

Du，Qiang,Luo，Jing,Yang，Mu Qing,et al. iNOS/NO is required for IRF1 activation in response to liver ischemia-reperfusion in mice[J]. MOLECULAR MEDICINE,2020,26(1).

Du，Qiang.,Luo，Jing.,Yang，Mu Qing.,Liu，Quan.,Heres，Caroline.,...&Geller，David A..(2020).iNOS/NO is required for IRF1 activation in response to liver ischemia-reperfusion in mice.MOLECULAR MEDICINE,26(1).

Du，Qiang,et al."iNOS/NO is required for IRF1 activation in response to liver ischemia-reperfusion in mice".MOLECULAR MEDICINE 26.1(2020).