A diagram illustrating the targets, and proposed effects on AKT activation and cell survival/proliferation of the inhibitors and activator.
The HDAC8 activator TM-2-51 and JMJD3 inhibitor GSK-J4 lead to an increase of H3K27me3 that suppress PTEN expression and enhances AKT activation. Direct inhibition of PTEN by VO-OHpic also induces AKT activation. In contrast, inhibition of HDAC8 by PCI34051 leads to expression of PTEN and inhibits AKT activation. Activation of AKT promotes cell survival/proliferation in LeTx-exposed monocytes/macrophages. Arrows indicate a positive effect or activation and blocked arrows indicate a negative effect or inhibition.
HDAC8 Prevents Anthrax Lethal Toxin-induced Cell Cycle Arrest through Silencing PTEN in Human Monocytic THP-1 Cells (Toxins, 2017)
Anthrax lethal toxin (LeTx) is a cytotoxic virulence factor that causes cell cycle arrest and cell death in various cell types. However, susceptibility to the cytotoxic effects varies depending on cell types. In proliferating monocytes, LeTx has only transient cytotoxic effects due to activation of the phosphoinositide 3-kinase (PI3K)-AKT-mediated adaptive responses. To date, the mechanism of LeTx in activating PI3K-AKT signaling axis is unknown. This study shows that the histone deacetylase 8 (HDAC8) is involved in activating PI3K-AKT signaling axis through down-regulating the phosphatase and tensin homolog 1 (PTEN) in human monocytic THP-1 cells. The HDAC8-specific activator TM-2-51 and inhibitor PCI-34051 enhanced and prevented, respectively, AKT activation and cell cycle progression in LeTx-treated cells. Furthermore, HDAC8 induced tri-methylation of histone H3 lysine 27 (H3K27me3), which is known to suppress PTEN expression, through at least in part down-regulating the H3K27me3 eraser Jumonji Domain Containing (JMJD) 3. Importantly, the JMJD3-specific inhibitor GSK-J4 induced AKT activation and protected cell cycle arrest in LeTx-treated cells, regardless the presence of HDAC8 activity. Collectively, this study for the first time demonstrated that HDAC8 activity determines susceptibility to cell cycle arrest induced by LeTx, through regulating the PI3K-PTEN-AKT signaling axis.
Adoptively transferred G-CSF generated BMDM exerts a protective effect on DSS-induced mouse colitis in G-CSFR-/-mice. G-CSFR+/+, and -/- mice were given 1.5% dextran sulfate sodium (DSS) in the drinking water for 5 days, and fresh water thereafter. G-CSFR-/- mice were injected with 5 × 106 M-CSF (20 ng/ml)-treated (BMDM) or M-CSF + G-CSF (10 ng/ml)-treated (G-BMDM) cells 1 day before and 2 days after DSS treatment. (A) Body weight loss, diarrhea/rectal bleeding, and overall colitis scores (encompassing weight loss, stool consistency, rectal bleeding, and loss of activity) were plotted from Day 0 to 10. *, p< 0.05 by one-way ANOVA with Tukey’s multiple comparison post hoc test. Symbols represent mean ± SEM. (B) Colon length of mice after 10 days of DSS treatment was measured and plotted. (C) Gut-homing phenotype of the adoptive transferred-M- and G-BMDM in DSS-treated G-CSFR-/- mice was evaluated by investigating the presence of mRNA expression of G-CSF receptor wild-type (G-CSFR exon 4 and 5) in colon tissues. Data shown as mean ± SEM [n ≥ 3; *, p < 0.05 by one-way ANOVA with Tukey’s multiple comparison post hoc test; columns accompanied by the same letter (a, b or c) are not significantly different from each other].
Protective role of G-CSF in dextran sulfate sodium-induced acute colitis through generating gut-homing macrophages (Cytokine, 2016)
Granulocyte colony-stimulating factor (G-CSF) is a pleiotropic cytokine best known for its role in promoting the generation and function of neutrophils. G-CSF is also found to be involved in macrophage generation and immune regulation; however, its in vivo role in immune homeostasis is largely unknown. Here, we examined the role of G-CSF in dextran sulfate sodium (DSS)-induced acute colitis using G-CSF receptor-deficient (G-CSFR-/-) mice. Mice were administered with 1.5 % DSS in drinking water for 5 days, and the severity of colitis was measured for the next 5 days. GCSFR-/- mice were more susceptible to DSS-induced colitis than G-CSFR+/+ or G-CSFR-/+ mice. G-CSFR-/- mice harbored less F4/80+ macrophages, but a similar number of neutrophils, in the intestine. In vitro, bone marrow-derived macrophages prepared in the presence of both G-CSF and macrophage colony-stimulating factor (M-CSF) (G-BMDM) expressed higher levels of regulatory macrophage markers such as programmed death ligand 2 (PDL2), CD71 and CD206, but not in arginase I, transforming growth factor (TGF)-β, Ym1 (chitinase-like 3) and FIZZ1 (found in inflammatory zone 1), and lower levels of inducible nitric oxide synthase (iNOS), CD80 and CD86 than bone marrow-derived macrophages prepared in the presence of M-CSF alone (BMDM), in response to interleukin (IL)-4/IL-13 and lipopolysaccharide (LPS)/interferon (IFN)-Ƴ, respectively. Adoptive transfer of G-BMDM, but not BMDM, protected G-CSFR-/- mice from DSS-induced colitis, and suppressed expression of tumor necrosis factor (TNF)-α, IL-1β and iNOS in the intestine. These results suggest that G-CSF plays an important role in preventing colitis, likely through populating immune regulatory macrophages in the intestine.