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

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• 作者：Ester Correia Sarmento Rios^a ; ^{estercsrios@yahoo.com.br" class="auth_mail" title="E-mail the corresponding author} ; Thais Martins de Lima^a ; Ana Iochabel Soares Moretti^b ; Francisco Garcia Soriano^a
• 关键词：Endotoxin ; Tolerance ; Gene transcription ; Endotoxemia
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：147
• 期：Complete
• 页码：110-116
• 全文大小：696 K

文摘

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 μM 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.