A critical role for p53 in the control of NF-kappaB-dependent gene expression in TLR4-stimulated dendritic cells exposed to Genistein.
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.
Dijsselbloem
Nathalie
N
Laboratory for Eukaryotic Gene Expression and Signal Transduction (LEGEST), Molecular Biology, Ghent University, Ghent, Belgium.
Goriely
Stanislas
S
Albarani
Valentina
V
Gerlo
Sarah
S
Francoz
Sarah
S
Marine
Jean-Christophe
JC
Goldman
Michel
M
Haegeman
Guy
G
Vanden Berghe
Wim
W
D000818:Animals; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D019833:Genistein / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016159:Tumor Suppressor Protein p53; D004247:DNA; D019833:Genistein