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Title
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A critical role for p53 in the control of NF-kappa B-dependent gene expression in TLR4-stimulated dendritic cells exposed to genistein
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Author
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Abstract
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| Considerable research has focused on the anti-inflammatory and antiproliferative activities exhibited by the soy isoflavone genistein. We previously demonstrated that genistein suppresses TNF-alpha-induced NF-kappa B-dependent IL-6 gene expression in cancer cells by interfering with the mitogen- and stress-activated protein kinase 1 activation pathway. However, effects of isoflavones on immune cells, such as dendritic cells, remain largely unknown. Here we show that genistein markedly reduces IL-6 cytokine production and transcription in LPS-stimulated human monocyte-derived dendritic cells. More particularly, we observe that genistein inhibits IL-6 gene expression by modulating the transcription factor NF-kappa B. Examination of NF-kappa B-related events downstream of TLR4 demonstrates that genistein affects NF-kappa B subcellular localization and DNA binding, although we observe only a minor inhibitory impact of genistein on the classical LPS-induced signaling steps. Interestingly, we find that genistein significantly increases p53 protein levels. We also show that overexpression of p53 in TLR4/MD2 HEK293T cells blocks LPS-induced NF-kappa B-dependent gene transcription, indicating the occurrence of functional cross-talk between p53 and NF-kappa B. Moreover, analysis of IL-6 mRNA levels in bone marrow-derived p53 null vs wild-type dendritic cells confirms a role for p53 in the reduction of NF-kappa B-dependentgene expression, mediated by genistein. |
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Language
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English
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Source (journal)
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The journal of immunology. - Baltimore, Md
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Publication
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Baltimore, Md
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2007
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ISSN
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0022-1767
[Print]
1550-6606
[Online]
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DOI
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10.4049/JIMMUNOL.178.8.5048
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Volume/pages
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178
:8
(2007)
, p. 5048-5057
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ISI
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000245605300047
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Full text (Publisher's DOI)
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