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

ABSTRACT: Inflammatory mediators activate the transcriptional complex HIF-1 (hypoxia-inducible factor-1), the key regulator of hypoxia-induced gene expression. Here we report that bacterial LPS (lipopolysaccharide) induces HIF-1alpha mRNA expression and HIF-1alpha protein accumulation in human monocytes as well as in non-differentiated and differentiated cells of the human monocytic cell line THP-1 under normoxic conditions. LPS and hypoxia synergistically activated HIF-1. Whereas LPS increased HIF-1alpha mRNA expression through activation of a NF-kappaB (nuclear factor kappaB) site in the promoter of the HIF-1alpha gene, hypoxia post-translationally stabilized HIF-1alpha protein. HIF-1alpha activation was followed by increased expression of the HIF-1 target gene encoding ADM (adrenomedullin). Knocking down HIF-1alpha by RNA interference significantly decreased ADM expression, which underlines the importance of HIF-1 for the LPS-induced ADM expression in normoxia. Simultaneously with HIF-1 activation, an increase in p44/42 MAPK (mitogen-activated protein kinase) phosphorylation was observed after incubation with LPS. In cells pretreated with the p44/42 MAPK inhibitor PD 98059 or with RNAi (interfering RNA) directed against p44/42 MAPK, LPS-induced HIF-1alpha accumulation and ADM expression were significantly decreased. From these results we conclude that LPS critically involves the p44/42 MAPK and NF-kappaB pathway in the activation of HIF-1, which is an important transcription factor for LPS-induced ADM expression.

SUBMITTER: Frede S

PROVIDER: S-EPMC1482811 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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

Frede Stilla S Stockmann Christian C Freitag Patricia P Fandrey Joachim J

The Biochemical journal 20060601 3

Inflammatory mediators activate the transcriptional complex HIF-1 (hypoxia-inducible factor-1), the key regulator of hypoxia-induced gene expression. Here we report that bacterial LPS (lipopolysaccharide) induces HIF-1alpha mRNA expression and HIF-1alpha protein accumulation in human monocytes as well as in non-differentiated and differentiated cells of the human monocytic cell line THP-1 under normoxic conditions. LPS and hypoxia synergistically activated HIF-1. Whereas LPS increased HIF-1alpha ...[more]

PMID: 16533170

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Project description:Background:Metabolic syndrome is characterized by macrophage infiltration and inflammatory responses-metaflammation in adipose tissue. IL-6 and IL-1? could mediate the inflammatory responses in macrophage stimulated-preadipocytes by modulating MAPK and NF-?B pathways. To test this hypothesis we used antibodies to block IL-6 and IL-1? action in macrophage conditioned medium (MacCM)-stimulated human white preadipocytes. Moreover, as interventions that prevent this could potentially be used to treat or prevent metabolic syndrome, and 1?,25(OH)2D3 has previously been reported to exert an anti-inflammatory action on macrophage-stimulated adipocytes, in this study we also investigated whether 1?,25(OH)2D3 could attenuate inflammatory responses in MacCM-stimulated preadipocytes, and explored the potential anti-inflammatory mechanisms. Methods:Human white preadipocytes were cultured with 25% MacCM for 24 h to elicit inflammatory responses. This was confirmed by measuring the concentrations and mRNA levels of major pro-inflammatory factors [IL-1?, IL-6, IL-8, monocyte chemoattractant protein (MCP)-1 and regulated on activation, normal T cell expressed and secreted (RANTES)] by ELISA and qPCR, respectively. IL-6 and IL-1? actions were blocked using IL-6 antibody (300 ng/ml) and IL-1? antibody (15 ?g/ml), respectively. Potential anti-inflammatory effects of 1?,25(OH)2D3 were investigated by pre-treatment and treatment of 1?,25(OH)2D3 (0.01 to 10 nM) for 48 h in MacCM-stimulated preadipocytes. In parallel, western blotting was used to determine inflammatory signaling molecules including relA of the NF-?B pathway and p44/42 MAPK modified during these processes. Results:MacCM enhanced the secretion and gene expression of IL-1?, IL-6, IL-8, MCP-1 and RANTES by increasing the phosphorylation levels of relA and p44/42 MAPK in preadipocytes, whereas blocking IL-6 and IL-1? action inhibited the inflammatory responses by decreasing p44/42 MAPK and relA phosphorylation, respectively. Furthermore, 10 nM of 1?,25(OH)2D3 generally inhibited the IL-6 and IL-1?-mediated inflammatory responses, and reduced both p44/42 MAPK and relA phosphorylation in MacCM-stimulated preadipocytes. Conclusions:1?,25(OH)2D3 attenuates IL-6 and IL-1?-mediated inflammatory responses, probably by inhibiting p44/42 MAPK and relA phosphorylation in MacCM-stimulated human white preadipocytes.

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

Publications

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

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