Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia

Fang, Hsin-Yu; Hughes, Russell; Murdoch, Craig; Coffelt, Seth B.; Biswas, Subhra K.; Harris, Adrian L.; Johnson, Randall S.; Imityaz, Hongxia Z.; Simon, M. Celeste; Fredlund, Erik; Greten, Florian R.; Rius, Jordi; Lewis, Claire E.

doi:10.1182/blood-2008-12-195941

Cited by 293 publications

(279 citation statements)

References 46 publications

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“…Unlike p38 and c-Jun, ERK 1/2 phosphorylation levels were not enhanced by palmitate treatment under hypoxia. Severe hypoxia, less than 1% O 2 , has been shown to activate the NF-B signaling pathway in macrophages (26,27). However, in our experiments, exposure to 1% O 2 did not enhance the levels of palmitate-induced p-IB␣ compared with normoxia (data not shown).…”

Section: Hypoxia Enhances Palmitate-induced Pro-inflammatory Cytokinecontrasting

confidence: 64%

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Snodgrass¹,

Boß²,

Zezina³

et al. 2016

Journal of Biological Chemistry

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Pro-inflammatory cytokines secreted by adipose tissue macrophages (ATMs) contribute to chronic low-grade inflammation and obesity-induced insulin resistance. Recent studies have shown that adipose tissue hypoxia promotes an inflammatory phenotype in ATMs. However, our understanding of how hypoxia modulates the response of ATMs to free fatty acids within obese adipose tissue is limited. We examined the effects of hypoxia (1% O 2 ) on the pro-inflammatory responses of human monocyte-derived macrophages to the saturated fatty acid palmitate. Compared with normoxia, hypoxia significantly increased palmitate-induced mRNA expression and protein secretion of IL-6 and IL-1␤. Although palmitate-induced endoplasmic reticulum stress and nuclear factor B pathway activation were not enhanced by hypoxia, hypoxia increased the activation of JNK and p38 mitogen-activated protein kinase signaling in palmitate-treated cells. Inhibition of JNK blocked the hypoxic induction of pro-inflammatory cytokine expression, whereas knockdown of hypoxia-induced transcription factors HIF-1␣ and HIF-2␣ alone or in combination failed to reduce IL-6 and only modestly reduced IL-1␤ gene expression in palmitate-treated hypoxic macrophages. Enhanced pro-inflammatory cytokine production and JNK activity under hypoxia were prevented by inhibiting reactive oxygen species generation. In addition, silencing of dual-specificity phosphatase 16 increased normoxic levels of IL-6 and IL-1␤ and reduced the hypoxic potentiation in palmitate-treated macrophages. The secretome of hypoxic palmitate-treated macrophages promoted IL-6 and macrophage chemoattractant protein 1 expression in primary human adipocytes, which was sensitive to macrophage JNK inhibition. Our results reveal that the coexistence of hypoxia along with free fatty acids exacerbates macrophage-mediated inflammation.

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Section: Hypoxia Enhances Palmitate-induced Pro-inflammatory Cytokinecontrasting

confidence: 64%

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Snodgrass¹,

Boß²,

Zezina³

et al. 2016

Journal of Biological Chemistry

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“…Previously published studies using primary human macrophages have demonstrated that in normoxic macrophages HIF-2α but not HIF-1α plays a dominant role in regulating VEGF transcription (33) whereas hypoxic macrophages rely on both HIF-1α and -2α for VEGF expression (34). This is in contrast to our study where we detected a significant increase in Vegf and Glut-1 transcripts, but no detectable levels of Hif-2α or Epo transcripts in monocytes of our myeloid-specific Vhl KO mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8

Ahn

Seita

Hong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von HippelLindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1-activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.

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“…Although TRAP1 is reported to be up-regulated in some cancers, its expression is diminished in others (8,(37)(38)(39). The impact of reduced TRAP1 expression on in vitro cell invasion raises the possibility that certain more aggressive, metastatic, or late-stage cancers may express less TRAP1 than less advanced tumors.…”

Section: Trap1 Expression Correlates Inversely With Tumor Stage In Cementioning

confidence: 99%

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

Yoshida

Tsutsumi²,

Mühlebach

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

235

272

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TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidation, and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial molecular chaperone may act as a tumor suppressor.M olecular chaperones help to maintain cellular homeostasis.The heat-shock protein 90 (HSP90) family of molecular chaperones is highly conserved from bacteria to mammals. HSP90 itself is an essential molecular chaperone found in the cytoplasm and nucleus of all eukaryotic cells (1, 2). In multicellular eukaryotes, the HSP90 family includes the mitochondrial chaperone TRAP1 (TNF receptor-associated protein), which shares 50% sequence similarity with HSP90. Although TRAP1 binds and hydrolyzes ATP in an analogous manner to HSP90 (3), its cellular function is less well understood. Thus, although many HSP90-dependent proteins ("clients") and interacting cochaperones have been described (www.picard.ch/downloads/Hsp90interactors.pdf), the validated list of TRAP1-dependent clients is quite small and TRAP1-interacting cochaperones, if they exist, have yet to be identified (4).Several studies have suggested that TRAP1 plays a cytoprotective role by buffering reactive oxygen species (ROS)-mediated oxidative stress (5, 6), and others have reported that TRAP1 overexpression attenuates ROS production (7). The antioxidant properties of TRAP1, together with its reported ability to regulate opening of the mitochondrial permeability transition pore (8, 9), may contribute to its antiapoptotic activity (4). For these reasons, TRAP1 has been proposed as an anticancer molecular target, and first-generation inhibitors have shown some anticancer activity in preclinical models (10). However, these inhibitors do not distinguish between HSP90 and TRAP1 (11), and TRAP1 expression in cancer is variable but HSP90 comprises as much as 5% of...

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Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia

Cited by 293 publications

References 46 publications

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

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