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Functional Interaction of HIF-1 and NF-kappaB Increasing the Transcriptional Activation of TNF-alpha Gene in Monocytes / 대한수혈학회지
Korean Journal of Blood Transfusion ; : 21-32, 2013.
Article in English | WPRIM | ID: wpr-173039
ABSTRACT

BACKGROUND:

Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine fulfilling a broad variety of immunoregulatory functions. Monocytes and macrophages play a pivotal role in inflammation and immune regulation. NF-kappaB and HIF-1 are known to increase expression of the TNF-alpha gene in a separate way.

METHODS:

Human monocytic leukemia, U937 cells, were transfected using the standard electroporation method for intracellular expression of NF-kappaB and HIF-1. We performed analysis using the mammalian two-hybrid assay and co-immunoprecipitation assay for detection of protein interaction of both proteins. In addition, chromatin immunoprecipitation analysis was performed for examination of NF-kappaB and HIF-1 binding on the TNF-alpha gene promoter.

RESULTS:

Here we show that NF-kappaB and HIF-1 cooperatively induced an increase in expression of the TNF-alpha gene dependent on promoter activity by the direct protein interaction of these two transcription factors. Hypoxia signaling induced marked enhancement of the transactivation of TNF-alpha promoter by HIF-1 and NF-kappaB. A tandem NF-kappaB/HIF-1 binding site was identified within the TNF-alpha promoter, which acted as a strong enhancer element. Physical association of the Rel domain of NF-kappaB and the N-TD domain of HIF-1 was required. Hypoxia treatment also resulted in a significant increase in the protein interaction of NF-kappaB and HIF-1 in vivo. Both transcription factors were recruited on the chromatin TNF-alpha promoter dependent on hypoxia stimuli.

CONCLUSION:

The results of this study indicate that a variety of extracellular signals for activation of TNF-alpha gene expression might converge on the transcriptional regulation through the NF-kappaB/HIF-1 signaling pathway.
Subject(s)

Full text: Available Index: WPRIM (Western Pacific) Main subject: Transcription Factors / Binding Sites / Chromatin / Monocytes / Leukemia / Proteins / Gene Expression / Transcriptional Activation / NF-kappa B / Enhancer Elements, Genetic Type of study: Prognostic study Limits: Humans Language: English Journal: Korean Journal of Blood Transfusion Year: 2013 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Transcription Factors / Binding Sites / Chromatin / Monocytes / Leukemia / Proteins / Gene Expression / Transcriptional Activation / NF-kappa B / Enhancer Elements, Genetic Type of study: Prognostic study Limits: Humans Language: English Journal: Korean Journal of Blood Transfusion Year: 2013 Type: Article