Expression profiles of genes involved in the mouse nuclear factor-kappa B signal transduction pathway are modulated by mangiferin.
The polyphenol mangiferin (MA) has been shown to have various effects on macrophage function, including inhibition of phagocytic activity and of free radical production. To further characterize the immunomodulatory activity of MA, this study investigated its effects on expression by activated mouse macrophages of diverse genes related to the NF-kappaB signaling pathway, using a DNA hybridization array containing 96 NF-kappaB-related genes and on cytokine levels using a cytokine protein array. MA at 10 microM significantly inhibited the expression of (a) two genes of the Rel/NF-kappaB/IkappaB family, RelA and RelB (=I-rel), indicating an inhibitory effect on NF-kappaB-mediated signal transduction; (b) TNF receptor-associated factor 6 (Traf6), indicating probable blockage of activation of the NF-kappaB pathway by lipopolysaccharide (LPS), tumor necrosis factor (TNF), and interleukin 1 (IL-1); (c) other proteins involved in responses to TNF and in apoptotic pathways triggered by DNA damage, including the TNF receptor (TNF-R), the TNF-receptor-associated death domain (TRADD), and the receptor interacting protein (RIP); (d) the extracellular ligand IL-1alpha, again indicating likely interference with responses to IL-1; (e) the pro-inflammatory cytokines IL-1, IL-6, IL-12, TNF-alpha and RANTES (CCL5), and cytokines produced by monocytes and macrophages, including granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF); (f) other toll-like receptor proteins (in addition to Traf6), including JNK1, JNK2 and Tab1; (g) Scya2 (small inducible cytokine A2=monocyte chemoattractant protein 1); and (h) various intracellular adhesion molecules (ICAMs), and the vascular cell adhesion molecule VCAM-1, which is locally increased in atheromas. The inhibition of JNK1, together with stimulation of c-JUN (i.e. the Jun oncogene) and the previously reported superoxide-scavenging activity of MA, suggests that MA may protect cells against oxidative damage and mutagenesis. Taken together, these results indicate that MA modulates the expression of a large number of genes that are critical for the regulation of apoptosis, viral replication, tumorogenesis, inflammation and various autoimmune diseases, and raise the possibility that it may be of value in the treatment of inflammatory diseases and/or cancer.
Leiro
José
J
Laboratorio de Parasitología, Instituto de Investigación y Análisis Alimentarios, Universidad de Santiago de Compostela, C/ Constantino Candeira s/n, 15782 Santiago de Compostela, La Coruña, Spain. mpleiro@usc.es
Arranz
Juan A
JA
Yáñez
Matilde
M
Ubeira
Florencio M
FM
Sanmartín
Manuel L
ML
Orallo
Francisco
F
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005122:Exudates and Transudates / Q000166:cytology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D017403:In Situ Hybridization; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D013864:Thioglycolates / Q000494:pharmacology; D044004:Xanthones / Q000494:pharmacology*
D000998:Antiviral Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D013864:Thioglycolates; D044004:Xanthones; C013592:mangiferin; D007371:Interferon-gamma; D004247:DNA