The role of nitric oxide in the epigenetic regulation of THP-1 induced by lipopolysaccharide

Author(s)

Sarmento Rios, Ester Correia ^[1] ; de Lima, Thais Martins ^[1] ; Soares Moretti, Ana Iochabel ^[2] ; Soriano, Francisco Garcia ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Sch Med, Dept Emergency Med, Ave Doutor Arnaldo, 455, Room 3189, BR-01246903 Sao Paulo, SP - Brazil

^[2] Inst Coracao, Ave Doutor Eneas de Carvalho Aguiar, 44 Cerqueira, BR-01246903 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Life Sciences; v. 147, p. 110-116, FEB 15 2016.
• Web of Science Citations: 5

Abstract

Aims: Changes in the gene expression are one of the molecular events involved in the Systemic of Inflammatory Response Syndrome during sepsis. The preconditioning with low doses of lipopolysaccharide (LPS) reduces the expression of pro-inflammatory genes leading to less tissue damage and better outcome. This hyporesponsive state called tolerance is associated to alterations in chromatin structure and nitric oxide (NO) production. In the current study, we demonstrated that tolerance induced by LPS was found to be NO-dependent and related to epigenetic changes. Main methods: THP-1 cells were cultivated in RPMI medium(Control), submitted to tolerance (500 ng/mL of LPS 24 h before challenge with 1000 ng/mL of LPS during 24 h Tolerant group) and challenge (1000 ng/mL of LPS during 24 h Directly challenged group). The analyses performed were: cytokines production, histone acetyl transferases/histone deacetylases (HAT/HDAC) activity, nitrosylation of HDAC-2 and -3, expression of acetylated histones H3 and H4. HDAC and Nitric Oxide Synthases (NOS) activities were inhibited with 30 mM trichostatin (TSA) and 100 mu M LNAME, respectively. Key findings: Administration of low doses of LPS repressed the production of IL-6 and IL-10, however this effect was abolished with the inhibition of NOS activity and by TSA in the case of IL-10. Tolerance modulates the activity of HAT and, consequently, the acetylation of histones H3 and H4. Inhibition of NO decreases acetylation of Histones. The HDACs 2 and 3 were nitrosylated after the tolerance induction. Significance: The tolerance to LPS regulates the cytokine production by modulating chromatin structure and this event is NO dependent. (C) 2016 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 09/16288-8 - Effect of tolerance to bacterial lipopolysaccharide on nitrosylation of DNA methyltransferase (DNMTs) and Histone deacetylases (HDACs)
• Grantee: Ester Correia Sarmento Rios
• Support Opportunities: Scholarships in Brazil - Post-Doctoral