Luteolin inhibits the nuclear factor-κB transcriptional activity in Rat-1 fibroblasts

Department of Life Science, Division of Molecular and Life Science and School of Environmental Science and Engineering, Pohang University of Science and Technology, San 31 Hyojadong, Nam-Gu, Pohang, Kyungbuk 790-784, South Korea.
Biochemical Pharmacology (Impact Factor: 5.01). 10/2003; 66(6):955-63. DOI: 10.1016/S0006-2952(03)00465-9
Source: PubMed


Flavonoids are natural polyphenolic compounds that have anti-inflammatory, cytoprotective and anticarcinogenic effects. In this study, we investigated the effects of several flavonoids on nuclear factor-kappa B (NF-kappa B) activation by using luciferase reporter gene assay. Among the flavonoids examined, luteolin showed the most potent inhibition on lipopolysaccharide (LPS)-stimulated NF-kappa B transcriptional activity in Rat-1 fibroblasts. Luteolin did not inhibit either I kappa B alpha degradation or NF-kappa B nuclear translocation, DNA binding or phosphorylation by LPS. However, luteolin prevented LPS-stimulated interaction between the p65 subunit of NF-kappa B and the transcriptional coactivator CBP. In addition, a specific PKA inhibitor that blocked the phosphorylation of CREB and c-Jun by luteolin partially reversed the inhibitory effect of luteolin on NF-kappa B.CBP complex formation and NF-kappa B transcriptional activity by LPS. These data imply that inhibition of NF-kappa B transcriptional activity by luteolin may occur through competition with transcription factors for coactivator that is available in limited amounts. Taken together, this study provides a molecular basis for the understanding of the anti-inflammatory effects of luteolin.

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    • "In addition, luteolin has been shown to inhibit the LPS-induced production of tumor necrosis factor alpha (TNF-α) and nitric oxide (NO) in an activated macrophage-like cell line (11). Luteolin also reduces the production of LPS-induced pro-inflammatory cytokines in intestinal epithelial cells, mouse bone marrow-derived dendritic cells (12), rat fibroblasts (13) and human gingival fibroblasts (14). Furthermore, in a previous study we observed that luteolin inhibited the secretion of several pro-inflammatory enzymes and pro-inflammatory cytokines by activated microglia (15). "
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    ABSTRACT: Microglial activation is one of the causative factors for neuroinflammation, which is associated with the pathophysiology of neurodegenerative diseases. Our previous study showed that the flavonoid luteolin inhibited several pro-inflammatory enzymes and pro-inflammatory cytokines that are induced by activated microglia; however, its effect on signaling pathways is currently unknown. The present study examined the effects of luteolin on signaling pathways stimulated by lipopolysaccharide (LPS), including Toll-like receptor-4 (TLR-4), nuclear transcription factor-κB (NF-κB), mitogen-activated protein kinase (MAPK) family and protein kinase B (Akt) pathways in murine microglial BV2 cells. In addition, BV2 microglia and SH-SY5Y neuroblastoma cells were cocultured to observe the indirect neuroprotective effects of luteolin. Luteolin inhibited the LPS-stimulated expression of TLR-4. In addition, luteolin blocked LPS-induced NF-κB, p38, JNK and Akt activation, but had no effect on ERK. When SH-SY5Y cells were cocultured with LPS-stimulated BV2 microglia, pretreatment with luteolin increased neuronal viability and reduced the number of apoptotic cells. These data suggest that luteolin has a beneficial effect on neuroinflammatory events in neurodegenerative diseases via suppression of the NF-κB, MAPK and Akt pathways in activated microglial cells.
    Full-text · Article · May 2014 · Experimental and therapeutic medicine
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    • "Flavonoids are polyphenolic compounds occurring in a wide range of plants, which can efficiently suppress the proliferation of tumor cells and induce apoptosis by blocking cell cycle progression [1], [2], [3], [4], [5]. Luteolin, 3′,4′,5,7-tetra-hydroxyflavone, is the flavone subclass of flavonoids isolated from celery, perilla leaf, camomile tea and green pepper [6]. Recently, luteolin has been found to possess a potent anticancer activity in several experiments, and even at low dosage it displays a marked effect on killing malignant cells [7], [8]. "
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    ABSTRACT: Background Abnormal activity of STAT3 is associated with a number of human malignancies. Hsp90 plays a central role in stabilizing newly synthesized proteins and participates in maintaining the functional competency of a number of signaling transducers involved in cell growth, survival and oncogenesis, such as STAT3. Hsp90 interacts with STAT3 and stabilizes Tyr-phosphorylated STAT3. It has been reported that luteolin possesses anticancer activity through degradation of Tyr705-phosphorylated STAT3. Methodology/Principal Findings We found that overexpression of Hsp90 inhibited luteolin-induced degradation of Tyr705-phosphorylated STAT3 and luteolin also reduced the levels of some other Hsp90 interacting proteins. Results from co-immunoprecipitation and immunoblot analysis demonstrated that luteolin prevented the association between Hsp90 and STAT3 and induced both Tyr705- and Ser727-phosphorylated STAT3 degradation through proteasome-dependent pathway. The molecular modeling analysis with CHARMm–Discovery Studio 2.1(DS 2.1) indicated that luteolin could bind to the ATP-binding pocket of Hsp90. SPR technology-based binding assay confirmed the association between luteolin and Hsp90. ATP-sepharose binding assay displayed that luteolin inhibited Hsp90-ATP binding. Conclusions/Significance Luteolin promoted the degradation of Tyr705- and Ser727-phosphorylated STAT3 through interacting with Hsp90 and induced apoptosis of cancer cells. This study indicated that luteolin may act as a potent HSP90 inhibitor in antitumor strategies.
    Full-text · Article · Nov 2012 · PLoS ONE
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    • "Luteolin has various biological activities for the prevention and treatment of chronic diseases [11-13]. Luteolin has antioxidant, anti-inflammatory, antimicrobial, cancer chemopreventive, cancer chemotherapeutic, and cardioprotective activities [4,6,7,9,11-15]. "
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    ABSTRACT: This study was performed to examine the feeding effects of Angelica keiskei Koidz (AK) and its processed products on serum, liver, and body fat content and the expression of antioxidant genes in rats fed a high fat diet. AK and its processed products were added at 3-5% to a high fat diet and fed to adult rats for 6 weeks. In experiment 1 (EXP 1), the rats were fed with one of six diets including a control diet (normal fat), high fat diet (HF), and HF + AK additives groups (four groups). In experiment 2 (EXP 2), the rats were separated into three groups of HF, HF + AK whole leaves, and HF + fermented juice (FS) + squeeze (SA). Body weight was not different among the groups in either experiment. The liver weight was lower in the FS and SA groups compared to that in the other groups (P < 0.05). Serum luteolin was higher in the AK and processed products groups compared to that in the HF group (P < 0.05). Gene expression of the antioxidative enzymes catalase and glutathione-s-reductase in the liver was higher in the AK processed products group than that in the other groups (P < 0.05). The results suggest that the intake of AK and its processed products increased the expression of antioxidant enzymes in animals fed a high fat diet, reduced hepatic cholesterol content, and increased the effective absorption of luteolin.
    Full-text · Article · Feb 2012 · Nutrition research and practice
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