Limits...
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.

Show MeSH

Related in: MedlinePlus

GSK3β activated LPS-induced glycolysis and HDAC4 degradation through NO. (A) BV2 cells were treated with a GSK3β inhibitor LiCl at indicated concentrations alone or with LPS (1 μg/ml) for 24 h. The levels of active caspase-3 and HDAC4 were determined by immunoblotting. LiCl markedly abolished LPS-induced caspase-3 activation and HDAC4 degradation. (B, C) BV2 cells were treated with LiCl (20 mM) and LPS alone or in combination as indicated. Glucose uptake assay was performed after 24 h of LPS treatment. LiCl markedly blunted LPS-induced glucose uptake and glycolysis, respectively (*p < 0.05 and **p < 0.01 vs. only LPS treatment). (D, E) BV2 cells were cotreated with LiCl (20 mM) and LPS for indicated times. iNOS protein expression and NO production were determined. LiCl strongly inhibited LPS-induced iNOS protein expression and NO production (***p < 0.001 vs. only LPS treatment). (F) BV2 cells were treated with indicated concentrations of an iNOS inhibitor, NAME, and LPS. Production of NO was strongly inhibited by NAME in a dose-dependent manner (***p < 0.001 vs. only LPS treatment). (G, H) BV2 cells were pretreated with indicated concentrations of an iNOS inhibitor, NAME, for 4 h, followed by LPS treatment for another 24 h. NAME pretreatment inhibited LPS-induced glucose uptake and glycolysis. (I) NAME pretreatment abolished LPS-induced caspase-3 activation and HDAC4 degradation (***p < 0.001 vs. only LPS treatment).
© Copyright Policy - creative-commons
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4214777&req=5

Figure 4: GSK3β activated LPS-induced glycolysis and HDAC4 degradation through NO. (A) BV2 cells were treated with a GSK3β inhibitor LiCl at indicated concentrations alone or with LPS (1 μg/ml) for 24 h. The levels of active caspase-3 and HDAC4 were determined by immunoblotting. LiCl markedly abolished LPS-induced caspase-3 activation and HDAC4 degradation. (B, C) BV2 cells were treated with LiCl (20 mM) and LPS alone or in combination as indicated. Glucose uptake assay was performed after 24 h of LPS treatment. LiCl markedly blunted LPS-induced glucose uptake and glycolysis, respectively (*p < 0.05 and **p < 0.01 vs. only LPS treatment). (D, E) BV2 cells were cotreated with LiCl (20 mM) and LPS for indicated times. iNOS protein expression and NO production were determined. LiCl strongly inhibited LPS-induced iNOS protein expression and NO production (***p < 0.001 vs. only LPS treatment). (F) BV2 cells were treated with indicated concentrations of an iNOS inhibitor, NAME, and LPS. Production of NO was strongly inhibited by NAME in a dose-dependent manner (***p < 0.001 vs. only LPS treatment). (G, H) BV2 cells were pretreated with indicated concentrations of an iNOS inhibitor, NAME, for 4 h, followed by LPS treatment for another 24 h. NAME pretreatment inhibited LPS-induced glucose uptake and glycolysis. (I) NAME pretreatment abolished LPS-induced caspase-3 activation and HDAC4 degradation (***p < 0.001 vs. only LPS treatment).

Mentions: Previously, GSK3β was implicated in HDAC4 degradation via an unknown mechanism (Cernotta et al., 2011). Because GSK3β is also a critical regulator in proinflammatory cytokine production (Martin et al., 2005), we asked whether GSK3β was involved in LPS-induced glycolysis and HDAC4 degradation. We found that GSK3β inhibitors LiCl (Figure 4A) and SB216763 (Supplemental Figure S1A) both effectively suppressed LPS-induced HDAC4 degradation (top), as well as caspase-3 activation (middle). Of importance, GSK3β inhibition also decreased glucose uptake and glycolysis in LPS-activated BV2 cells (Figure 4, B and C, and Supplemental Figure S1B). These results indicate that GSKβ signaling is critical for LPS-induced glycolysis, caspase-3 activation, and HDAC4 degradation.


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)

GSK3β activated LPS-induced glycolysis and HDAC4 degradation through NO. (A) BV2 cells were treated with a GSK3β inhibitor LiCl at indicated concentrations alone or with LPS (1 μg/ml) for 24 h. The levels of active caspase-3 and HDAC4 were determined by immunoblotting. LiCl markedly abolished LPS-induced caspase-3 activation and HDAC4 degradation. (B, C) BV2 cells were treated with LiCl (20 mM) and LPS alone or in combination as indicated. Glucose uptake assay was performed after 24 h of LPS treatment. LiCl markedly blunted LPS-induced glucose uptake and glycolysis, respectively (*p < 0.05 and **p < 0.01 vs. only LPS treatment). (D, E) BV2 cells were cotreated with LiCl (20 mM) and LPS for indicated times. iNOS protein expression and NO production were determined. LiCl strongly inhibited LPS-induced iNOS protein expression and NO production (***p < 0.001 vs. only LPS treatment). (F) BV2 cells were treated with indicated concentrations of an iNOS inhibitor, NAME, and LPS. Production of NO was strongly inhibited by NAME in a dose-dependent manner (***p < 0.001 vs. only LPS treatment). (G, H) BV2 cells were pretreated with indicated concentrations of an iNOS inhibitor, NAME, for 4 h, followed by LPS treatment for another 24 h. NAME pretreatment inhibited LPS-induced glucose uptake and glycolysis. (I) NAME pretreatment abolished LPS-induced caspase-3 activation and HDAC4 degradation (***p < 0.001 vs. only LPS treatment).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4214777&req=5

Figure 4: GSK3β activated LPS-induced glycolysis and HDAC4 degradation through NO. (A) BV2 cells were treated with a GSK3β inhibitor LiCl at indicated concentrations alone or with LPS (1 μg/ml) for 24 h. The levels of active caspase-3 and HDAC4 were determined by immunoblotting. LiCl markedly abolished LPS-induced caspase-3 activation and HDAC4 degradation. (B, C) BV2 cells were treated with LiCl (20 mM) and LPS alone or in combination as indicated. Glucose uptake assay was performed after 24 h of LPS treatment. LiCl markedly blunted LPS-induced glucose uptake and glycolysis, respectively (*p < 0.05 and **p < 0.01 vs. only LPS treatment). (D, E) BV2 cells were cotreated with LiCl (20 mM) and LPS for indicated times. iNOS protein expression and NO production were determined. LiCl strongly inhibited LPS-induced iNOS protein expression and NO production (***p < 0.001 vs. only LPS treatment). (F) BV2 cells were treated with indicated concentrations of an iNOS inhibitor, NAME, and LPS. Production of NO was strongly inhibited by NAME in a dose-dependent manner (***p < 0.001 vs. only LPS treatment). (G, H) BV2 cells were pretreated with indicated concentrations of an iNOS inhibitor, NAME, for 4 h, followed by LPS treatment for another 24 h. NAME pretreatment inhibited LPS-induced glucose uptake and glycolysis. (I) NAME pretreatment abolished LPS-induced caspase-3 activation and HDAC4 degradation (***p < 0.001 vs. only LPS treatment).
Mentions: Previously, GSK3β was implicated in HDAC4 degradation via an unknown mechanism (Cernotta et al., 2011). Because GSK3β is also a critical regulator in proinflammatory cytokine production (Martin et al., 2005), we asked whether GSK3β was involved in LPS-induced glycolysis and HDAC4 degradation. We found that GSK3β inhibitors LiCl (Figure 4A) and SB216763 (Supplemental Figure S1A) both effectively suppressed LPS-induced HDAC4 degradation (top), as well as caspase-3 activation (middle). Of importance, GSK3β inhibition also decreased glucose uptake and glycolysis in LPS-activated BV2 cells (Figure 4, B and C, and Supplemental Figure S1B). These results indicate that GSKβ signaling is critical for LPS-induced glycolysis, caspase-3 activation, and HDAC4 degradation.

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