Induction of IκBα Expression as a Mechanism Contributing to the Anti-inflammatory Activities of Peroxisome Proliferator-activated Receptor-α Activators

Delerive, Philippe; Gervois, Philippe; Fruchart, Jean‐Charles; Staels, Bart

doi:10.1074/jbc.m004045200

Cited by 434 publications

(291 citation statements)

References 46 publications

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“…Alternatively, inhibitory effects might occur through competitive binding of transcriptional coactivators by PPAR or by PPAR -induced transcription factors. Moreover, longer exposure to fibrates was found to induce I B mRNA and protein expression in primary smooth muscle cells and hepatocytes (Delerive et al, 2000). Future study should investigate these inhibitory effects of fibrates via PPAR on chenodeoxycholic acid-induced RANTES expression in human hepatocytes.…”

Section: Discussionmentioning

confidence: 91%

Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-κB activation

Hirano

Fujii

et al. 2002

European Journal of Pharmacology

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Fibrates, hypolipidemic agents, are reported to be effective in treatment of primary biliary cirrhosis. However, the mechanism involved in therapeutic benefits of fibrates in primary biliary cirrhosis remains unknown. In contrast, hepatic regulated upon activation, normal T-cell expressed and secreted (RANTES) is increased in patients with primary biliary cirrhosis and bile acids up-regulate RANTES expression in hepatocytes. The role of fibrates in bile acid-induced RANTES expression was investigated in human hepatoma cells; 100 µM of bezafibrate and fenofibrate decreased expression of chenodeoxycholic acid-induced RANTES mRNA and protein. In addition, luciferase enzyme assay using RANTES promoter-luciferase reporter plasmid revealed that 100 µM of bezafibrate and fenofibrate transcriptionally reduced chenodeoxycholic acid-induced RANTES gene expression. Moreover, bezafibrate clearly repressed DNA-binding activity of nuclear factor-B (NF-B) induced by chenodeoxycholic acid. Therefore, fibrates might be inhibitory agents of inflammatory cell migration by RANTES to the liver in patients with primary biliary cirrhosis, possibly indicating that fibrates are therapeutic agents in primary biliary cirrhosis.

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Section: Discussionmentioning

confidence: 91%

Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-κB activation

Hirano

Fujii

et al. 2002

European Journal of Pharmacology

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“…Studies by Daynes and colleagues (31) have shown that in vivo administration of PPAR␣ ligands to aged mice diminishes their augmented NF-B levels. Fibrates may also inhibit NF-B DNA binding activity by augmenting the expression of I B␣ (32). In addition, in vivo administration of WY14,643 to aged mice corrects the dysregulation of IFN-␥ and splenic inducible NO synthase, as well as the elevated splenocyte levels of IL-6 and IL-12 (31, 33).…”

Section: Discussionmentioning

confidence: 99%

WY14,643, a PPARα Ligand, Has Profound Effects on Immune Responses In Vivo

Cunard

DiCampli

Archer

et al. 2002

The Journal of Immunology

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with diverse actions. PPARα and PPARγ are expressed in different lymphocyte subpopulations. Recently, we have observed that PPARα ligands elicit augmented IL-4 expression in cultures of mitogen-activated splenocytes. The following studies were undertaken to characterize the in vivo effects of WY14,643, a PPARα ligand. Our studies demonstrate that oral administration of WY14,643 markedly reduces splenocyte number in immunized and nonimmunized C57BL/6 mice. Mice fed WY14,643 display impaired IgG responses to myelin oligodendrocyte glycoprotein peptide 35–55 (pMOG35–55), following immunization with pMOG35–55/CFA. Following in vitro restimulation with pMOG35–55, splenocytes harvested from WY14,643-fed mice demonstrate impaired production of IFN-γ, IL-6, and TNF-α despite similar proliferative responses. We also demonstrate higher expression of PPARα in B than T cells. Finally, to obtain an understanding of the cause of splenocyte depletion with fibrate therapy, we studied the effect of WY14,643 on apoptosis of activated splenocytes. WY14,643 in vitro induces apoptosis in lymphocytes and this effect appears to occur in a PPARα-independent manner. Thus WY14,643, a fibrate, is a profound immunosuppressive agent.

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“…33 PPARa may also increase the level of nuclear IkBa, leading to reduction in NF-kB DNAbinding activity. 34 In contrast to the abundant information on the suppressive effect of PPARa on NF-kB, little is known about anti-inflammatory effects of other PPARs. In vascular smooth muscle cells and endothelial cells, previous reports showed that, in contrast to PPARa agonists, PPARg agonists did not influence cytokine-induced activation of NF-kB.…”

Section: Selective Loss Of Adipocytes By Tnf-a M Tamai Et Almentioning

confidence: 99%

Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

Tamai

Shimada

Hiramatsu

et al. 2010

Laboratory Investigation

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Tumor necrosis factor-a (TNF-a) is a key regulator of adipose tissue mass, but mechanisms underlying this effect have not been fully elucidated. We found that exposure to TNF-a caused a significant decrease in the number of adipocytes, but not preadipocytes. Subsequent experiments revealed that TNF-a selectively deleted adipocytes through induction of apoptosis. Following exposure to TNF-a, rapid activation of nuclear factor-kB (NF-kB) was observed only in preadipocytes, but not in adipocytes. Inhibition of NF-kB rendered preadipocytes susceptible to TNF-a-induced apoptosis, suggesting that different activity of NF-kB is the determinant for the distinct apoptotic responses. During adipocyte differentiation, expression and activity of peroxisome proliferator-activated receptor-g (PPARg) were upregulated. Treatment of preadipocytes with a PPARg agonist attenuated NF-kB activation and rendered the cells vulnerable to TNF-a-induced apoptosis. Conversely, treatment of adipocytes with a PPARg antagonist enhanced NF-kB activation and conferred resistance to TNF-a-induced apoptosis, suggesting involvement of PPARg in the suppression of NF-kB in adipocytes. We also found that, following differentiation, expression and activity of CCAAT/ enhancer binding protein (C/EBP), especially C/EBPa and C/EBPb, were upregulated in adipocytes. Overexpression of individual C/EBPs significantly inhibited activation of NF-kB in preadipocytes. Furthermore, transfection with siRNA for C/EBPa or C/EBPb enhanced activity of NF-kB in adipocytes, suggesting that C/EBP is also involved in the repression of NF-kB in adipocytes. These results suggested novel mechanisms by which TNF-a selectively deletes adipocytes in the adipose tissue. The C/EBP-and PPARg-mediated suppression of NF-kB may contribute to TNF-a-related loss of adipose tissue mass under certain pathological situations, such as cachexia.

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Induction of IκBα Expression as a Mechanism Contributing to the Anti-inflammatory Activities of Peroxisome Proliferator-activated Receptor-α Activators

Cited by 434 publications

References 46 publications

Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-κB activation

Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-κB activation

WY14,643, a PPARα Ligand, Has Profound Effects on Immune Responses In Vivo

Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

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