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During the inflammatory response at least 2 transcription factors, NF-kB and AP-1, are involved in the altered profile of gene expression. We used human hepatoma (HepG2) and human umbilical vein endothelial cells (HUVEC) as a model system: NF-kB and AP-1 were activated by the proinflammatory cytokine IL-1 in the absence or presence of 21 selected plant extracts and the effect was evaluated by the electrophoretic mobility shift assay (EMSA). In both types of cells activation of NFkB by IL-1 was significantly inhibited by extracts from Scandix australis and Artemisia alba, whereas extracts from Amaranthus sp., Eryngium campestre, Thymus pulegioides and Reichardia picroides elicited cell-type dependent response. The IL-1-induced AP-1 activation was diminished by extracts from Scandix australis, Amaranthus sp. and Artemisia alba more potently in HUVEC, while extracts from Urospermum picroides and Scandix pecten-veneris in HepG2 cells. Inhibitory activities of plant extracts towards cytokine activated NF-kB and AP-1 depend to some extent on the order of addition of IL-1 and plant extract to the cell culture, but the mechanism of action of extract components is not clear: although plant polyphenols may participate they are unlikely to be the only mediators, and MAP kinases were found generally not involved in down-regulation of transcription factors activity by plant extracts.
In the retinoic acid-differentiated neuroblastoma SH-SY5Y cells, IL-1 induced bind­ing activity of NFkB and up-regulated the expression and activity of MnSOD. The IL-1-elicited effects were partly reversed by IL-4 and IL-6. It is proposed that IL-4 and IL-6 may participate in the regulation of the imbalanced oxidant status induced by IL-1 in differentiated neuroblastoma cells. In the SH-SY5Y cell line, TNFa neither ac­tivated NFkB nor induced MnSOD expression and activity, but was capable of modu­lating the IL-1 effects. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NFkB acti­vation, down-regulated the expression and activity of MnSOD, which may suggest that the regulation of MnSOD by IL-1 in retinoic acid-differentiated neuroblastoma cells was mediated by the nuclear factor kB.
Recent investigations suggest that proinflammatory cytokines such as IL-6 and IL-8 are involved in the development of colorectal cancer (CRC), whereas statins, primarily used to decrease high levels of blood cholesterol, exhibit pleiotropic effects on carcinogenesis. In the present study we compared the expression of IL-8 and IL-6 in tissue samples of tumor and adjacent normal colon mucosa obtained from patients with advanced colorectal cancer (CRC). The analysis of mRNAs expression for these proinflammatory cytokines determined by RT-PCR showed a higher level of IL-8-mRNA in tumor tissue than in normal mucosa, while IL-6 was similarly expressed in tumor and normal tissue. The mean values of serum levels of both IL-6 and IL-8 were significantly higher in CRC patients than in healthy volunteers. Surgical removal of the tumor resulted in a prompt decrease of serum level of IL-8 already on the third day, whereas IL-6 level was transiently increased to become lower only after 7-10 days. Treatment of CRC with simvastatin (80 mg/day for 14 days) led to a significant decrease of serum IL-6, while the IL-8 level was less affected. The in vitro experiments on colorectal cancer-derived cell lines (HT-29 and Caco-2) demonstrated that application of simvastatin decreased generation of both IL-6 and IL-8. The differences in response of serum levels of IL-6 and IL-8 after tumor removal and treatment with simvastatin are novel observations suggesting distinct pathological roles of the two cytokines in CRC development. We conclude that 1) colorectal carcinogenesis is accompanied by increased synthesis and release of proinflammatory cytokines such as IL-6 and IL-8; 2) simvastatin therapy results in a decrease in serum level of proinflammatory cytokines, especially IL-6 in CRC and 3) simvastatin inhibits release of IL-8 and IL-6 from colorectal cell lines.
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