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Inhibition of ERK1/2 by silymarin in mouse mesangial cells
Cha Kyung Youn1, Sung Il Cho2, Min Young Lee3
1Department of Premedical Sciences, Chosun University College of Medicine, Gwangju 61452, Korea.
Abstract:
The present study aimed to show that pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-1β] synergistically induce the production of nitric oxide (NO) production in mouse mesangial cells, which play an important role in inflammatory glomerular injury. We also found that co-treatment with cytokines at low doses (TNF-α; 5 ng/ml, IFN-γ; 5 ng/ml, and IL-1β; 1.25 U/ml) synergistically induced NO production, whereas treatment with each cytokine alone did not increase NO production at doses up to 100 ng/ml or 50 U/ml. Silymarin, a polyphenolic flavonoid isolated from milk thistle (Silybum marianum), attenuates cytokine mixture (TNF-α, IFN-γ, and IL-1β)-induced NO production. Western blot and RT-PCR analyses showed that silymarin inhibits inducible nitric oxide synthase (iNOS) expression in a dose-dependent manner. Silymarin also inhibited extracellular signal-regulated protein kinase-1 and -2 (ERK1/2) phosphorylation. Collectively, we have demonstrated that silymarin inhibits NO production in mouse mesangial cells, and may act as a useful anti-inflammatory agent.
Insights
Pro-inflammatory cytokines synergistically increase nitric oxide (NO) in kidney cells. Silymarin, a milk thistle compound, effectively reduces this NO production by inhibiting inducible nitric oxide synthase (iNOS).
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-1 beta (IL-1β), are implicated in inflammatory glomerular injury.
- Nitric oxide (NO) production by mesangial cells plays a critical role in these inflammatory processes.
Purpose of the Study:
- To investigate the synergistic effect of TNF-α, IFN-γ, and IL-1β on nitric oxide (NO) production in mouse mesangial cells.
- To evaluate the potential of silymarin, a flavonoid from milk thistle (Silybum marianum), as an inhibitor of cytokine-induced NO production and its underlying mechanisms.
Main Methods:
- Mouse mesangial cells were treated with combinations of TNF-α, IFN-γ, and IL-1β at varying concentrations.
- Nitric oxide production was measured.
- Silymarin's effects on NO production, inducible nitric oxide synthase (iNOS) expression (via Western blot and RT-PCR), and extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation were assessed.
Main Results:
- Low-dose co-treatment with TNF-α, IFN-γ, and IL-1β synergistically induced significant NO production, while individual cytokines did not at higher doses.
- Silymarin effectively attenuated the synergistic NO production induced by the cytokine mixture.
- Silymarin demonstrated a dose-dependent inhibition of iNOS expression and reduced ERK1/2 phosphorylation.
Conclusions:
- Pro-inflammatory cytokines synergistically stimulate NO production in mouse mesangial cells, contributing to inflammatory kidney injury.
- Silymarin exhibits anti-inflammatory properties by inhibiting NO production, likely through the downregulation of iNOS expression and modulation of signaling pathways like ERK1/2.
- Silymarin shows promise as a therapeutic agent for inflammatory kidney diseases.
