Thalidomide in Rat Liver Cirrhosis: Blockade of Tumor Necrosis Factor-α via Inhibition of Degradation of an Inhibitor of Nuclear Factor-κB

Paul, Shelley Chireyath; Lv, Ping; Xiao, Yan-Jv; An, Ping; Liu, Shiquan; Luo, Hao

doi:10.1159/000094492

Cited by 17 publications

(14 citation statements)

References 92 publications

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“…Previous studies also demonstrated that thalidomide has inhibitory effects on TNF-α secretion by unstimulated peripheral blood cells treated for two days [13]. Thalidomide may curtail TNF-α production by inhibiting degradation of the inhibitor of kappa B (IκB) and thus, NF-κB-mediated expression of TNF-α mRNA [24]. Here, we also detected downregulation of TNF-α production by LPS-stimulated MΦ after thalidomide treatment.…”

Section: Discussionsupporting

confidence: 73%

Effects of immunomodulatory drugs on TNF-α and IL-12 production by purified epidermal langerhans cells and peritoneal macrophages

et al. 2011

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BackgroundLangerhans cells constitute a special subset of immature dendritic cells localized in the epidermis that play a key role in the skin's immune response. The production of cytokines is a key event in both the initiation and the regulation of immune responses, and different drugs can be used to remove or modify their production by DC and, therefore, alter immune responses in a broad spectrum of diseases, mainly in human inflammatory and autoimmune diseases. In the present study, we examined the effects of prednisone, thalidomide, cyclosporine A, and amitriptyline, drugs used in a variety of clinical conditions, on the production of TNF-α, IL-10, and IL-12 by purified epidermal Langerhans cells and peritoneal macrophages in BALB/c mice.FindingsAll drugs inhibited TNF-α production by Langerhans cells after 36 hours of treatment at two different concentrations, while prednisone and thalidomide decreased IL-12 secretion significantly, amitriptyline caused a less pronounced reduction and cyclosporine A had no effect. Additionally, TNF-α and IL-12 production by macrophages decreased, but IL-10 levels were unchanged after all treatments.ConclusionsOur results demonstrate that these drugs modulate the immune response by regulating pro-inflammatory cytokine production by purified epidermal Langerhans cells and peritoneal macrophages, indicating that these cells are important targets for immunosuppression in various clinical settings.

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Section: Discussionsupporting

confidence: 73%

Effects of immunomodulatory drugs on TNF-α and IL-12 production by purified epidermal langerhans cells and peritoneal macrophages

et al. 2011

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“…[32][33][34][35][36] Suppression of NF-κB activation may represent a target for the prevention and treatment of liver fibrosis. 32,36) It has been generally accepted that the expression of α-SMA in HSCs increases in CCl 4 -induced acute liver injury. 35,37,38) In this study, gomisin A inhibited the increase in the hepatic mRNA and protein levels of α-SMA.…”

Section: Discussionmentioning

confidence: 99%

The Molecular Mechanisms of the Hepatoprotective Effect of Gomisin A against Oxidative Stress and Inflammatory Response in Rats with Carbon Tetrachloride-Induced Acute Liver Injury

Teraoka

Shimada

Aburada

2012

Biological & Pharmaceutical Bulletin

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Oxidative damage and inflammation are implicated in the pathogenesis of liver injury and fibrosis. In the present study, we investigated the molecular mechanism by which gomisin A conferred a hepatoprotective effect, focusing on its antioxidant and anti-inflammatory effects using rats with carbon tetrachloride (CCl 4 )-induced acute liver injury. Pretreatment with gomisin A prior to the administration of CCl 4 markedly prevented an increase in alanine aminotransferase, aspartate aminotransferase, and histological hepatic lesions. Gomisin A was also associated with a decrease in hepatic lipid peroxidation, and increased superoxide dismutase activity, suggesting that gomisin A has an antioxidant effect. In addition gomisin A treatment ameliorated mRNA levels of CCl 4 -induced inflammatory mediators, including tumor necrosis factor-α, interleukin-1β and inducible nitric oxide (NO) synthase, and the protein levels of transcriptional upregulator nuclear factor kappa B (NF-κB) and phospho-inhibitor of NF-κB (IκB). Furthermore, α-smooth muscle actin (α-SMA), a myofibroblast marker, was also inhibited by gomisin A treatment. These results suggest that gomisin A inhibits the oxidative stress and activation of NF-κB, leading to down-regulation of pro-inflammatory mediators and amelioration of fibrogenesis.Key words gomisin A; oxidative stress; inflammatory response; carbon tetrachloride; acute liver injuryThe liver has the important function of metabolizing and eliminating biological and xenobiotic compounds. Liver injury is considered to be a serious health problem leading to acute hepatitis, cholestasis, and cirrhosis. Hepatocellular injury usually leads to oxidative stress, inflammation, and activation of the innate immune system. These factors lead to the release of pro-inflammatory cytokines (that can result in hepatic necrosis) and of pro-fibrogenic cytokines that may cause increased synthesis of extracellular matrix components by activation of quiescent hepatic stellate cells (HSCs).

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“…8 Therefore, the effect of thalidomide on LPS-induced NF-kB activation was examined in RAW 264.7 cells (Fig. 2).…”

Section: Thalidomide Inhibits the Activation Of Nf-kb In Lps-stimulatmentioning

confidence: 99%

Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-α production via down-regulation of MyD88 expression

et al. 2009

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The effect of thalidomide on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-a production was studied by using RAW 264.7 murine macrophage-like cells. Thalidomide significantly inhibited LPS-induced TNF-a production. Thalidomide prevented the activation of nuclear factor (NF)-kB by down-regulating phosphorylation of inhibitory kB factor (IkB), and IkB kinase (IKK)-a and IKK-b Moreover, thalidomide inhibited LPS-induced phosphorylation of AKT, p38 and stress-activated protein kinase (SAPK)/JNK. The expression of myeloid differentiation factor 88 (MyD88) protein and mRNA was markedly reduced in thalidomide-treated RAW 264.7 cells but there was no significant alteration in the expression of interleukin-1 receptor-associated kinase (IRAK) 1 and TNF receptor-associated factor (TRAF) 6 in the cells. Thalidomide did not affect the cell surface expression of Toll-like receptor (TLR) 4 and CD14, suggesting the impairment of intracellular LPS signalling in thalidomide-treated RAW 264.7 cells. Thalidomide significantly inhibited the TNF-a production in response to palmitoyl-Cys(RS)-2,3-di(palmitoyloxy) propyl)-Ala-Gly-OH (Pam 3 Cys) as a MyD88-dependent TLR2 ligand. Therefore, it is suggested that thalidomide might impair LPS signalling via down-regulation of MyD88 protein and mRNA and inhibit LPS-induced TNF-a production. The putative mechanism of thalidomide-induced MyD88 down-regulation is discussed.

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Thalidomide in Rat Liver Cirrhosis: Blockade of Tumor Necrosis Factor-α via Inhibition of Degradation of an Inhibitor of Nuclear Factor-κB

Cited by 17 publications

References 92 publications

Effects of immunomodulatory drugs on TNF-α and IL-12 production by purified epidermal langerhans cells and peritoneal macrophages

Effects of immunomodulatory drugs on TNF-α and IL-12 production by purified epidermal langerhans cells and peritoneal macrophages

The Molecular Mechanisms of the Hepatoprotective Effect of Gomisin A against Oxidative Stress and Inflammatory Response in Rats with Carbon Tetrachloride-Induced Acute Liver Injury

Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-α production via down-regulation of MyD88 expression

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