A critical role for p53 in the control of NF-kappaB-dependent gene expression in TLR4-stimulated dendritic cells exposed to Genistein.

Abstract

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-kappaB-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-kappaB. Examination of NF-kappaB-related events downstream of TLR4 demonstrates that genistein affects NF-kappaB 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-kappaB-dependent gene transcription, indicating the occurrence of functional cross-talk between p53 and NF-kappaB. 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-kappaB-dependent gene expression, mediated by genistein.

• Authors: Nathalie Dijsselbloem, Stanislas Goriely, Valentina Albarani, Sarah Gerlo, Sarah Francoz, Jean-Christophe Marine, Michel Goldman, Guy Haegeman, Wim Vanden Berghe
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 178 Issue 8 Pg. 5048-57 (Apr 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17404287 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Lipopolysaccharides
• NF-kappa B
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Tumor Suppressor Protein p53
• DNA
• Genistein

Topics

• Animals
• DNA (metabolism)
• Dendritic Cells (drug effects, metabolism)
• Gene Expression Regulation
• Genistein (pharmacology)
• Interleukin-6 (biosynthesis, genetics)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (physiology)
• Promoter Regions, Genetic
• Signal Transduction (drug effects)
• Toll-Like Receptor 4 (physiology)
• Tumor Suppressor Protein p53 (physiology)