Abstract 20947: Dnmt and Hdac Inhibitors Together Inhibits Lps Induced Cell Death by Modulating Stat3 Jmjd3 Signaling Axis

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Abstract

Introduction: Inflammation associated with acute lung injury (ALI) is caused by direct insult to the lungs or by sepsis, which is responsible for tissue damage and cell death. Although the therapeutic effectiveness of epigenetic modifiers can potentially limit lung inflammation, few studies have examined the combinatorial (Aza+TSA) use of a DNA methyl transferase (DNMT) inhibitor, Aza (5-Aza 2-deoxycytidine), and histone deacetylase (HDAC) inhibitor, TSA (Trichostatin A), on the recovery of cell death mechanisms in macrophages.

Hypothesis: Therapy with Aza+TSA will reduce cell death by interfering with phosphorylation of JNK and ERK and thereby inhibit JMJD3 expression.

Methods and Results: In an LPS-induced ALI mouse model, a single dose of Aza+TSA prevented lung inflammation and injury with significant reduction in mortality as compared with mice treated with either Aza or TSA alone (Thangavel J 2014). DNA ladder analysis shows a decrease in the DNA breaks in LPS-induced bone marrow derived macrophages (BMDMs) treated with Aza+TSA when compared to untreated LPS control (Fig. A). There is also a reduction in phosphorylation of JNK and ERK in LPS-induced BMDMs when treated together compared to untreated or treated with either Aza or TSA alone. This reduction is caused by the decrease in JMJD3 expression when STAT3 was pulled down after the combined treatment of Aza+TSA, emphasizing the involvement of STAT3-JMJD3 signaling in inflammation associated cell death mechanism (Fig. B).

Conclusions: LPS acts on macrophages through activation of the MAPK pathway followed by the modulation of STAT3-JMJD3 associated with cell death. Administration of DNMT and HDAC inhibitor together interrupts STAT3-mediated decrease in the JMJD3 signaling pathway and cell death in BMDM. !--[endif]-->

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