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      Proinflammatory Cytokine-Induced NF-κB Activation in Human Mesangial Cells Is Mediated through Intracellular Calcium but Not ROS: Effects of Silymarin

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          Background: It is not fully understood whether intracellular calcium and/or reactive oxygen species (ROS) are involved in nuclear factor-ĸB (NF-ĸB) activation by proinflammatory cytokines. Silymarin exhibits anti-inflammatory and antioxidant effects but the effect of silymarin in human mesangial cells is largely unknown. Method: NF-ĸB binding activity was measured by electrophoretic mobility shift assay. Intracellular calcium was monitored by confocal microscopy using Fluo-3 and intracellular ROS production was determined by flow cytometry. Monocyte chemoattractant protein-1 (MCP-1) expression was measured by Northern blot analysis and ELISA. Results: NF-ĸB was activated within 30 min by tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). Intracellular ROS was not produced until 30 min and also antioxidants such as N-acetylcysteine and tiron had no effect on the TNF-α- or IL-1β-induced NF-ĸB activation. Intracellular calcium was increased by TNF-α and IL-1β. Furthermore, a calcium chelator, BAPTA-AM, attenuated the NF-ĸB activation. Silymarin dose-dependently inhibited the TNF-α- or IL-1β-induced NF-ĸB activation and MCP-1 expression. Silymarin also inhibited TNF-α-induced intracellular calcium. Conclusions: Induction of NF-ĸB within 30 min by TNF-α- and IL-1β was mediated through intracellular calcium but not ROS. Silymarin inhibited TNF-α-induced calcium-dependent NF-ĸB activation irrespective of its antioxidant effect.

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          Most cited references 19

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          Nuclear Factor Kb: An Oxidative Stress-Responsive Transcription Factor of Eukaryotic Cells (A Review)

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            Evidence that reactive oxygen species do not mediate NF-kappaB activation.

            It has been postulated that reactive oxygen species (ROS) may act as second messengers leading to nuclear factor (NF)-kappaB activation. This hypothesis is mainly based on the findings that N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), compounds recognized as potential antioxidants, can inhibit NF-kappaB activation in a wide variety of cell types. Here we reveal that both NAC and PDTC inhibit NF-kappaB activation independently of antioxidative function. NAC selectively blocks tumor necrosis factor (TNF)-induced signaling by lowering the affinity of receptor to TNF. PDTC inhibits the IkappaB-ubiquitin ligase activity in the cell-free system where extracellular stimuli-regulated ROS production does not occur. Furthermore, we present evidence that endogenous ROS produced through Rac/NADPH oxidase do not mediate NF-kappaB signaling, but instead lower the magnitude of its activation.
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              Silibinin protects mice from T cell-dependent liver injury.

              Silibinin is the major pharmacologically active compound of the Silybum marianum fruit extract silymarin. Its well-known hepatoprotective activities are mostly explained by antioxidative properties, inhibition of phosphatidylcholine synthesis or stimulation of hepatic RNA and protein synthesis. Here, we characterized the hepatoprotective potential of silibinin as an immune-response modifier in T cell-dependent hepatitis in vivo. Silibinin was tested in the mouse model of concanavalin A (ConA)-induced, T cell-dependent hepatitis. Liver injury was assessed by quantification of plasma transaminase activities and intrahepatic DNA fragmentation. Plasma cytokine concentrations were determined by enzyme-linked immunosorbent assay (ELISA), intrahepatic cytokine and inducible NO synthase (iNOS) mRNA levels by reverse transcriptase polymerase chain reaction, intrahepatic iNOS expression by immunofluorescent staining, and intrahepatic nuclear factor kappa B (NF-kappaB) activation by electrophoretic mobility shift assay. Silibinin significantly inhibited ConA-induced liver disease. Silibinin proved to be an immune-response modifier in vivo, inhibiting intrahepatic expression of tumor necrosis factor, interferon-gamma, interleukin (IL)-4, IL-2, and iNOS, and augmenting synthesis of IL-10. In addition, silibinin inhibited intrahepatic activation of NF-kappaB. Silibinin, suppressing T cell-dependent liver injury as an immune-response modifier, might be a valuable drug in therapeutic situations in which intrahepatic immunosuppression is required.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                July 2006
                21 April 2006
                : 103
                : 4
                : e156-e165
                Department of Internal Medicine, Urology and Asan Institute for Life Sciences, College of Medicine, University of Ulsan, Seoul, Korea
                92906 Nephron Exp Nephrol 2006;103:e156–e165
                © 2006 S. Karger AG, Basel

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                Figures: 9, References: 26, Pages: 1
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