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Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production.

Wang B, Liu TY, Lai CH, Rao YH, Choi MC, Chi JT, Dai JW, Rathmell JC, Yao TP - Mol. Biol. Cell (2014)

Bottom Line: Inhibition of GSK3β or iNOS suppresses nitric oxide (NO) production, glycolysis, and HDAC4 degradation.We present evidence that sustained glycolysis induced by LPS treatment activates caspase-3, which cleaves HDAC4 and triggers its degradation.Of importance, a caspase-3-resistant mutant HDAC4 escapes LPS-induced degradation and prolongs inflammatory cytokine production.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710 Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.

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HDAC4 was degraded after prolonged LPS treatment. (A) BV2 cells were treated with LPS (1 μg/ml) for indicated times, followed by immunoblotting with antibodies for HDAC4, HDAC5, HDAC7, and α-tubulin as indicated. Note that HDAC4, but not HDAC5 or HDAC7, was markedly reduced after prolonged LPS treatment (18–24 h). (B) HDAC4 mRNA level was checked by real-time PCR after LPS treatment. LPS only modestly affected HDAC4 mRNA after LPS treatment. (C) Bone marrow–derived primary macrophages were treated with LPS (1 μg/ml) at indicated times, followed by immunoblotting for HDAC4. Note that HDAC4 protein level also was decreased after LPS treatment for 24 and 36 h.
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Figure 2: HDAC4 was degraded after prolonged LPS treatment. (A) BV2 cells were treated with LPS (1 μg/ml) for indicated times, followed by immunoblotting with antibodies for HDAC4, HDAC5, HDAC7, and α-tubulin as indicated. Note that HDAC4, but not HDAC5 or HDAC7, was markedly reduced after prolonged LPS treatment (18–24 h). (B) HDAC4 mRNA level was checked by real-time PCR after LPS treatment. LPS only modestly affected HDAC4 mRNA after LPS treatment. (C) Bone marrow–derived primary macrophages were treated with LPS (1 μg/ml) at indicated times, followed by immunoblotting for HDAC4. Note that HDAC4 protein level also was decreased after LPS treatment for 24 and 36 h.

Mentions: Although HDAC4 is required for inflammatory cytokine production, a time-course analysis revealed that HDAC4 level in BV2 cells was markedly reduced after prolonged LPS treatment (18–24 h; Figure 2A). This effect is specific, as the closely related class IIA HDAC members HDAC5 and HDAC7 were not affected by the same treatment (Figure 2A). HDAC4 mRNA level was not obviously affected by LPS treatment (Figure 2B). A similar loss of HDAC4 was also apparent in primary bone marrow–derived macrophages challenged by LPS (Figure 2C). These results show that prolonged LPS treatment leads to HDAC4 degradation in macrophages.


Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production.

Wang B, Liu TY, Lai CH, Rao YH, Choi MC, Chi JT, Dai JW, Rathmell JC, Yao TP - Mol. Biol. Cell (2014)

HDAC4 was degraded after prolonged LPS treatment. (A) BV2 cells were treated with LPS (1 μg/ml) for indicated times, followed by immunoblotting with antibodies for HDAC4, HDAC5, HDAC7, and α-tubulin as indicated. Note that HDAC4, but not HDAC5 or HDAC7, was markedly reduced after prolonged LPS treatment (18–24 h). (B) HDAC4 mRNA level was checked by real-time PCR after LPS treatment. LPS only modestly affected HDAC4 mRNA after LPS treatment. (C) Bone marrow–derived primary macrophages were treated with LPS (1 μg/ml) at indicated times, followed by immunoblotting for HDAC4. Note that HDAC4 protein level also was decreased after LPS treatment for 24 and 36 h.
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Related In: Results  -  Collection

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Figure 2: HDAC4 was degraded after prolonged LPS treatment. (A) BV2 cells were treated with LPS (1 μg/ml) for indicated times, followed by immunoblotting with antibodies for HDAC4, HDAC5, HDAC7, and α-tubulin as indicated. Note that HDAC4, but not HDAC5 or HDAC7, was markedly reduced after prolonged LPS treatment (18–24 h). (B) HDAC4 mRNA level was checked by real-time PCR after LPS treatment. LPS only modestly affected HDAC4 mRNA after LPS treatment. (C) Bone marrow–derived primary macrophages were treated with LPS (1 μg/ml) at indicated times, followed by immunoblotting for HDAC4. Note that HDAC4 protein level also was decreased after LPS treatment for 24 and 36 h.
Mentions: Although HDAC4 is required for inflammatory cytokine production, a time-course analysis revealed that HDAC4 level in BV2 cells was markedly reduced after prolonged LPS treatment (18–24 h; Figure 2A). This effect is specific, as the closely related class IIA HDAC members HDAC5 and HDAC7 were not affected by the same treatment (Figure 2A). HDAC4 mRNA level was not obviously affected by LPS treatment (Figure 2B). A similar loss of HDAC4 was also apparent in primary bone marrow–derived macrophages challenged by LPS (Figure 2C). These results show that prolonged LPS treatment leads to HDAC4 degradation in macrophages.

Bottom Line: Inhibition of GSK3β or iNOS suppresses nitric oxide (NO) production, glycolysis, and HDAC4 degradation.We present evidence that sustained glycolysis induced by LPS treatment activates caspase-3, which cleaves HDAC4 and triggers its degradation.Of importance, a caspase-3-resistant mutant HDAC4 escapes LPS-induced degradation and prolongs inflammatory cytokine production.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710 Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.

Show MeSH
Related in: MedlinePlus