Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB

Frede, Stilla; Stockmann, Christian; Freitag, Patrícia; Fandrey, Joachim

doi:10.1042/bj20051839

Cited by 377 publications

(353 citation statements)

References 43 publications

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“…A number of stimuli have been shown to upregulate HIF mRNA expression through NF-kB-dependent mechanisms (21,22). Indeed, a recent publication has implicated an absolute necessity of basal canonical NF-kB signaling for HIF expression (23).…”

Section: Discussionmentioning

confidence: 99%

An Intact Canonical NF-κB Pathway Is Required for Inflammatory Gene Expression in Response to Hypoxia

Fitzpatrick

Tambuwala

Brüning

et al. 2011

The Journal of Immunology

131

107

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Hypoxia is a feature of the microenvironment in a number of chronic inflammatory conditions due to increased metabolic activity and disrupted perfusion at the inflamed site. Hypoxia contributes to inflammation through the regulation of gene expression via key oxygen-sensitive transcriptional regulators including the hypoxia-inducible factor (HIF) and NF-κB. Recent studies have revealed a high degree of interdependence between HIF and NF-κB signaling; however, the relative contribution of each to hypoxia-induced inflammatory gene expression remains unclear. In this study, we use transgenic mice expressing luciferase under the control of NF-κB to demonstrate that hypoxia activates NF-κB in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-κB, we confirm a unidirectional dependence of hypoxic HIF-1α accumulation upon an intact canonical NF-κB pathway in cultured cells. Cyclooxygenase-2 and other key proinflammatory genes are transcriptionally induced by hypoxia in a manner that is both HIF-1 and NF-κB dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-κB pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1α and the p65 subunit of NF-κB directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-κB signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression.

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Section: Discussionmentioning

confidence: 99%

An Intact Canonical NF-κB Pathway Is Required for Inflammatory Gene Expression in Response to Hypoxia

Fitzpatrick

Tambuwala

Brüning

et al. 2011

The Journal of Immunology

131

107

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show abstract

“…While the role of hydroxylases in the hypoxic sensitivity of the HIF pathway has been clearly demonstrated, recent data raises the intriguing possibility that components of the NF-κB pathway may also be substrates of hydroxylases including PHD1 and FIH [33][34]. It is interesting to note that as well as being hypoxia sensitive, both the HIF and NF-κB pathways are regulated by inflammatory mediators including cytokines and bacterial products such as lippopolysaccharide [35][36] (Fig. 4).…”

Section: Signaling Interactions Between Hypoxia and Inflammationmentioning

confidence: 99%

Hypoxia and gastrointestinal disease

2007

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The gastrointestinal mucosa is a richly perfused vascular bed directly juxtaposed with the anaerobic and nonsterile lumen of the gut. As such, intestinal epithelial cells, which line the mucosa, experience a uniquely steep physiologic oxygen gradient in comparison with other cells of the body. Inflammation associated with a loss of epithelial barrier function and unregulated exposure of the mucosal immune system to luminal antigens leads to inflammatory bowel disease (IBD), a relatively common disorder with severe morbidity and a limited therapeutic repertoire. During IBD, increased tissue metabolism and vasculitis renders the chronically inflamed mucosa and particularly the epithelium hypoxic, giving rise to the activation of the hypoxia-responsive transcription factor hypoxia-inducible factor (HIF). Recent studies utilizing conditional intestinal epithelial hif1a-null mice have revealed a protective role for epithelial HIF-1α in murine models of IBD. Such protection occurs, at least in part, through HIF-dependent induction of barrier-protective genes in the epithelium. More recently, studies employing pharmacologic activation of HIF via inhibition of HIF prolyl hydroxylases revealed a profoundly protective effect of these agents in murine models of colitis. In this paper, we review this pathway in detail and examine the therapeutic potential for targeting HIF hydroxylases in intestinal mucosal inflammatory disease.

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“…Other studies have reported that HIF-1␣ expression is regulated by either transcriptional or translational mechanisms. In macrophages and monocytes, mRNA level of HIF-1␣ is induced by LPS (Blouin et al, 2004;Frede et al, 2006). In PC12 cells, HIF-1␣ translational efficiency is increased during hypoxia (Hui et al, 2006).…”

mentioning

confidence: 99%

Hypoxia-Inducible Factor-1α Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression

Yeh¹,

Hung²,

Gean³

et al. 2008

J. Neurosci.

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Inflammation is involved in some neurodegenerative disorders. NMDA glutamate receptors play an important role in neuronal development. Here, we show that NR1 expression in the cerebral cortex and primary neurons of rats was upregulated after lipopolysaccharide (LPS) treatment. This increase in NR1 expression was considered to be strongly associated with hypoxia-inducible factor-1␣ (HIF-1␣) activation because the treatment of primary neurons with either echinomycin or small interfering RNA (siRNA) targeting HIF-1␣ could block NR1 expression. HIF-1␣ could be induced by an increase in the translational efficiency of the cells. After this, it was transported into the nucleus where it bound to the NR1 promoter and regulated the induction of NR1 transcriptional activity by LPS. LPS injection into the prefrontal cortex caused neuronal death, and this condition was aggravated by intracerebroventricular injection of echinomycin. Furthermore, knockdown of HIF-1␣ and NR1 by the appropriate siRNAs reduced the neurite outgrowth and viability of the primary neurons. These results suggest that NR1 expression is regulated by HIF-1␣ and plays a protective role in neurons during LPS challenge.

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Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB

Cited by 377 publications

References 43 publications

An Intact Canonical NF-κB Pathway Is Required for Inflammatory Gene Expression in Response to Hypoxia

An Intact Canonical NF-κB Pathway Is Required for Inflammatory Gene Expression in Response to Hypoxia

Hypoxia and gastrointestinal disease

Hypoxia-Inducible Factor-1α Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression

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