Effects of Arsenic Trioxide on INF-gamma Gene Expression in MRL/lpr Mice and Human Lupus
- 132 Downloads
Arsenic trioxide (As2O3; ATO), a traditional Chinese medicine, is used to treat patients with acute promye-locytic leukemia, while its application for treatment of systemic lupus erythematosus (SLE) is still under evaluation. The high expression of INF-gamma (INF-γ) is a primary pathogenic factor in SLE. It is found that ATO can reduce INF-γ expression levels in lupus-prone mice, whereas it is not clear whether ATO has the same effect on SLE patients. Therefore, this study was to investigate the underlying mechanism of the effects of ATO on the expression of INF-γ in splenocytes of MRL/lpr mice and PBMCs of human lupus. The mRNA and protein expression levels of INF-γ were assessed by real-time RT-PCR and ELISA, respectively. The histone acetylation status of the INF-γ promoter and the binding of RNA polymerase II (RNA Pol II) to the INF-γ promoter were detected using a chromatin immunoprecipitation (ChIP) technique. The mRNA and protein expression levels of INF-γ decreased in both splenocytes of MRL/lpr mice and PBMCs of SLE patients with ATO treatment, which were accompanied by reduced histone H4 and H3 acetylation in INF-γ promoter and decreased combination of RNA Pol II to the INF-γ promoter. Therefore, ATO may reduce the expression level of the INF-γ by altering the levels of INF-γ promoter acetylation and the combination of RNA Pol II to the INF-γ promoter in splenocytes of MRL/lpr mice and PBMCs of SLE patients.
KeywordsArsenic trioxide INF-gamma Systemic lupus erythematosus Acetylation RNA polymerase II
We thank Prof. Kang Yu (Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University) for providing assistance with experimental techniques.
Compliance with Ethical Standards
This study was carried out with approval of the Ethics Committee of First Affiliated Hospital, Wenzhou Medical University.
Conflict of Interest
The authors declare that they have no competing interests.
- 5.Mannis G, Logan A, Leavitt A, Yanada M, Hwang J, Olin R, Damon L, Andreadis C, Ai W, Gaensler K (2015) Delayed hema-topoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis. Bone Marrow Transplant 50(1):40–44. https://doi.org/10.1038/bmt.2014.201 CrossRefPubMedGoogle Scholar
- 13.Prud'homme GJ (2000) Gene therapy of autoimmune diseases with vectors encoding regulatory cytokines or inflammatory cytokine inhibitors. J Gene Med 2(4):222–232. https://doi.org/10.1002/1521-2254(200007/08)2:4<222::AID-JGM117>3.0.CO;2-P CrossRefPubMedGoogle Scholar
- 17.Dai R, Zhang Y, Khan D, Heid B, Caudell D, Crasta O, Ahmed SA (2010) Identification of a common lupus disease-associated microRNA expression pattern in three different murine models of lupus. PLoS One 5(12):e14302. https://doi.org/10.1371/journal.pone.0014302 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Bauer JW, Petri M, Batliwalla FM, Koeuth T, Wilson J, Slattery C, Panoskaltsis-Mortari A, Gregersen PK, Behrens TW, Baechler EC (2009) Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. Arthritis Rheum 60(10):3098–3107. https://doi.org/10.1002/art.24803 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Bauer JW, Baechler EC, Petri M, Batliwalla FM, Crawford D, Ortmann WA, Espe KJ, Li W, Patel DD, Gregersen PK, Behrens TW (2006) Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med 3(12):e491. https://doi.org/10.1371/journal.pmed.0030491 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Backs J, Olson EN (2006) Control of cardiac growth by histone acetylation/deacetylation. Circ Res 98(1):15–24. https://doi.org/10.1161/01.RES.0000197782.21444.8f CrossRefPubMedGoogle Scholar
- 35.Sandoval J, Rodriguez JL, Tur G, Serviddio G, Pereda J, Boukaba A, Sastre J, Torres L, Franco L, Lopez-Rodas G (2004) RNAPol-ChIP: a novel application of chromatin immunoprecipitation to the analysis of real-time gene transcription. Nucleic Acids Res 32(11):e88. https://doi.org/10.1093/nar/gnh091 CrossRefPubMedPubMedCentralGoogle Scholar