Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 101, Issue 3, Pages 633-642Publisher
OXFORD UNIV PRESS
DOI: 10.1189/jlb.2HI1115-491R
Keywords
innate immunity; binge drinking; TLR4 tolerance; HDAC1
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Funding
- National Science Foundation of China [81273526, 81473268]
- Anhui Provincial Key Scientific and Technological Project [1301042212]
- Anhui Provincial Natural Science Foundation [1308085MH145, 1508085QH170]
- Specialized Research Fund for the Doctoral Program of Higher Education [20123420120001]
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Acute ethanol exposure decreases the production of LPS-induced TNF-, and the migration of monocytes and macrophages via ATF3. Binge drinking represses host innate immunity and leads to a high risk of infection. Acute EtOH-pretreated macrophages exhibit a decreased production of proinflammatory mediators in response to LPS. ATF3 is induced and counter-regulates the LPS/TLR4 inflammatory cascade. Here, we investigated the potential role of ATF3 in LPS tolerance in acute ethanol-pretreated macrophages. We found that there was an inverse correlation between ATF3 and LPS-induced TNF- production in acute ethanol-pretreated murine monocytes and macrophages. The knockdown of ATF3 attenuated the inhibitory effects of acute ethanol treatment on LPS-induced TNF- production. Furthermore, ChIP assays and co-IP demonstrated that ATF3, together with HDAC1, negatively modulated the transcription of TNF-. In binge-drinking mice challenged with LPS, an up-regulation of ATF3 and HDAC1 and a concomitant decrease in TNF- were observed. Given that HDAC1 was concomitantly induced in acute ethanol-exposed monocytes and macrophages, we used the HDACi TSA or silenced HDAC1 to explore the role of HDAC1 in acute ethanol-treated macrophages. Our results revealed that TSA treatment and HDAC1 knockdown prevented acute ethanol-induced ATF3 expression and the inhibition of TNF- transcription. These data indicated a dual role for HDAC1 in acute ethanol-induced LPS tolerance. Furthermore, we showed that the induction of ATF3 led to the impaired migration of BM monocytes and macrophages. Overall, we present a novel role for ATF3 in the inhibition of LPS-induced TNF- and in the impairment of monocyte and macrophage migration.
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