AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

Namgaladze, Dmitry; Snodgrass, Ryan G.; Angioni, Carlo; Grossmann, Nina; Dehne, Nathalie; Geißlinger, Gerd; Brüne, Bernhard

doi:10.1074/jbc.m115.678243

Cited by 32 publications

(20 citation statements)

References 46 publications

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“…Inhibitor concentrations were previously described in the literature. ALOX15 was chosen because of its possible expression sensitivity to metabolic perturbations through regulation by the central metabolic sensor AMP-activated protein kinase (23). MDMs were pre-incubated with ACLY inhibitors for 1 h followed by 24 h-treatment with IL-4 in the presence of inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Polarization of Human Macrophages by Interleukin-4 Does Not Require ATP-Citrate Lyase

et al. 2018

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Macrophages exposed to the Th2 cytokines interleukin (IL) IL-4 and IL-13 exhibit a distinct transcriptional response, commonly referred to as M2 polarization. Recently, IL-4-induced polarization of murine bone marrow-derived macrophages (BMDMs) has been linked to acetyl-CoA levels through the activity of the cytosolic acetyl-CoA-generating enzyme ATP-citrate lyase (ACLY). Here, we studied how ACLY regulated IL-4-stimulated gene expression in human monocyte-derived macrophages (MDMs). Although multiple ACLY inhibitors attenuated IL-4-induced target gene expression, this effect could not be recapitulated by silencing ACLY expression. Furthermore, ACLY inhibition failed to alter cellular acetyl-CoA levels and histone acetylation. We generated ACLY knockout human THP-1 macrophages using CRISPR/Cas9 technology. While these cells exhibited reduced histone acetylation levels, IL-4-induced gene expression remained intact. Strikingly, ACLY inhibitors still suppressed induction of target genes by IL-4 in ACLY knockout cells, suggesting off-target effects of these drugs. Our findings suggest that ACLY may not be the major regulator of nucleocytoplasmic acetyl-CoA and IL-4-induced polarization in human macrophages. Furthermore, caution should be warranted in interpreting the impact of pharmacological inhibition of ACLY on gene expression.

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Section: Resultsmentioning

confidence: 99%

Polarization of Human Macrophages by Interleukin-4 Does Not Require ATP-Citrate Lyase

et al. 2018

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“…HIF1α can be pharmacologically activated by the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). Since activated AMPK attenuates STAT3-dependent transcription induced by IL-6 or IL-4 9 , 29 , we blocked AICAR conversion to ZMP using ABT-702. Figure 4 shows that the ability of AICAR to inhibit activation of gene expression is stimulus-dependent.…”

Section: Resultsmentioning

confidence: 99%

AICAR inhibits NFκB DNA binding independently of AMPK to attenuate LPS-triggered inflammatory responses in human macrophages

Kirchner

Brüne

Namgaladze

2018

Sci Rep

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5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is an established pharmacological activator of AMP-activated protein kinase (AMPK). Both, AICAR and AMPK were reported to attenuate inflammation. However, AICAR is known for many AMPK-independent effects, although the mechanisms remain incompletely understood. Here we report a potent suppression of lipopolysaccharide (LPS)-induced inflammatory gene expression by AICAR in primary human macrophages, which occurred independently of its conversion to AMPK-activating 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate. Although AICAR did not interfere with activation of cytosolic signalling cascades and nuclear translocation of nuclear factor - κB (NFκB) by LPS, it prevented the recruitment of NFκB and RNA polymerase II to target gene promoters. AICAR also inhibited signal transducer and activator of transcription 3 (STAT3)-dependent induction of interleukin (IL) IL-6 and IL-10 targets, while leaving STAT6 and HIF1α-dependent gene expression in IL-4 and dimethyloxalylgylcine-treated macrophages intact. This points to a transcription factor-specific mode of action. Attenuated gene expression correlated with impaired NFκB and STAT3, but not HIF-binding in electrophoretic mobility shift assays in vitro. Conclusively, AICAR interferes with DNA binding of NFκB and STAT3 to modulate inflammatory responses.

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“…Based on RNA sequencing results, DEGs, such as ALOX15, Bcl2l15 and Nat8l, were found to be downregulated in the APCP group and upregulated in the NECA group compared with the model group. Namgaladze et al (48) reported that suppressing ALOX15 expression might promote an anti-inflammatory phenol type of IL-4-stimulated human macrophages. Additionally, Kleinstein et al (24) demonstrated that genetic variability in 5-lipoxygenase-activating protein and ALOX15 might affect the risk of colorectal neoplasia, particularly for rectal cancer.…”

Section: Discussionmentioning

confidence: 99%

CD73 promotes colitis‑associated tumorigenesis in mice

Liu

Lan

et al. 2020

Oncol Lett

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Patients with inflammatory bowel disease (IBD) are at a higher risk of developing colitis-associated colorectal cancer. The aim of the present study was to investigate the role of CD73 in IBD-associated tumorigenesis. A mouse model of colitis-associated tumorigenesis (CAT) induced by azoxymethane and dextran sulfate sodium was successfully constructed. Model mice were injected with CD73 inhibitor or adenosine receptor agonist. Colon length, body weight loss and tumor formation were assessed macroscopically. Inflammatory cytokine measurement and RNA sequencing on colon tissues were performed. Inhibition of CD73 by adenosine 5'-(α,β-methylene) diphosphate (APCP) suppressed the severity of CAT with attenuated weight loss, longer colons, lower tumor number and smaller tumor size compared with the model group. Activation of adenosine receptors using 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-β-D-ribofuranur onamide (NECA) exacerbated CAT. Histological assessment indicated that inhibition of CD73 reduced, while activation of adenosine receptors exacerbated, the histological damage of the colon. Increased expression of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6) in colonic tissue was detected in the NECA group. According to RNA sequencing results, potential oncogenes such as arachidonate 15-lipoxygenase (ALOX15), Bcl-2-like protein 15 (Bcl2l15) and N-acetylaspartate synthetase (Nat8l) were downregulated in the APCP group and upregulated in the NECA group compared with the model group. Therefore, inhibition of CD73 attenuated IBD-associated tumorigenesis, while activation of adenosine receptors exacerbated tumorigenesis in a C57BL/6J mouse model. This effect may be associated with the expression of pro-inflammatory cytokines and the regulation of ALOX15, Bcl2l15 and Nat8l.

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AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

Cited by 32 publications

References 46 publications

Polarization of Human Macrophages by Interleukin-4 Does Not Require ATP-Citrate Lyase

Polarization of Human Macrophages by Interleukin-4 Does Not Require ATP-Citrate Lyase

AICAR inhibits NFκB DNA binding independently of AMPK to attenuate LPS-triggered inflammatory responses in human macrophages

CD73 promotes colitis‑associated tumorigenesis in mice

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