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

Hirano, Yoshiko; Hirano, Fuminori; Fujii, Hiroshi; Makino, Isao

doi:10.1016/s0014-2999(02)01902-7

Cited by 22 publications

(18 citation statements)

References 49 publications

(37 reference statements)

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“…Blockade of CCR1 with the CCR1-specific antagonist BX471 substantially reduced interstitial leukocyte accumulation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome (41). Our observations demonstrating that the use of a PPAR␣ ligand WY significantly inhibited cisplatin-induced upregulation of RANTES, and RANTES's recep- tors CCR1 and CCR5 are in agreement with those previous studies where fibrates were shown to repress TNF-␣ and bile acids induced RANTES expression in human hepatocytes through inhibition of both DNA binding activity and transcriptional activation of NF-B (22,24). Nevertheless, our studies cannot rule out the possibility that other inflammatory cells such as macrophages or T cells, in addition to neutrophils, participate in the inflammatory process associated with cisplatin nephrotoxicity.…”

Section: Role Of Inflammation In Cisplatin-induced Injurysupporting

confidence: 91%

Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF

Gökden²,

Okusa³

et al. 2005

American Journal of Physiology-Renal Physiology

122

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Recently, we demonstrated that peroxisome proliferator-activated receptor-alpha (PPARalpha) ligand ameliorates cisplatin-induced acute renal failure (ARF) by preventing inhibition of substrate oxidation, and also by preventing apoptosis and necrosis of the proximal tubule (Li S, Bhatt R, Megyesi J, Gokden N, Shah SV, and Portilla D. Am J Physiol Renal Physiol 287: F990-F998, 2004). In the following studies, we examined the protective effect of PPARalpha ligand on cisplatin-induced inflammatory responses during ARF. Mice subjected to a single intraperitoneal injection of cisplatin developed ARF at day 3. Cisplatin increased mRNA and protein expression of TNF-alpha, RANTES, and also upregulated endothelial adhesion molecules ICAM-1/VCAM-1 and chemokine receptors CCR1/CCR5. Cisplatin also led to neutrophil infiltration in the corticomedullary region. Pretreatment of wild-type mice with WY-14,643, a fibrate class of PPARalpha ligands, before cisplatin significantly suppressed cisplatin-induced upregulation of cytokine/chemokine expression, prevented neutrophil accumulation, and ameliorated renal dysfunction. In contrast, treatment with PPARalpha ligand before cisplatin did not prevent cytokine/chemokine production, neutrophil accumulation, and did not protect kidney function in PPARalpha null mice. In addition, we observed that cisplatin-induced NF-kappaB binding activity in nuclear extracts from wild-type mice was markedly reduced by treatment with PPARalpha ligand. These results demonstrate that PPARalpha exerts an anti-inflammatory effect in kidney tissue by a mechanism that includes inhibition of NF-kappaB DNA binding activity, and this effect results in inhibition of neutrophil infiltration, cytokine/chemokine release, and amelioration of cisplatin-induced ARF.

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Section: Role Of Inflammation In Cisplatin-induced Injurysupporting

confidence: 91%

Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF

Gökden²,

Okusa³

et al. 2005

American Journal of Physiology-Renal Physiology

122

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“…The maintenance of intestinal homeostasis is complex and involves interactions among the intestinal microflora, the epithelium and the host immune system. It has previously been shown that the leukotriene B 4 -PPARα pathway controls inflammation [7] and that PPARα ligands inhibit the migration of inflammatory cells [8]. In addition, we have reported that a PPARγ ligand inhibited the immunological functions of macrophages [9,10].…”

Section: Introductionmentioning

confidence: 75%

PPARα contributes to colonic protection in mice with DSS-induced colitis

Azuma

Nishiyama

Matsuo

et al. 2010

International Immunopharmacology

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“…Bezafibrate and fenofibrate decrease the chenodeoxycholic acid- and tumor necrosis factor-α-induced mRNA expression and production of RANTES protein in human hepatoma cells [30, 31]. These findings indicate that fibrates may inhibit inflammatory cell migration by RANTES to the liver in patients with PBC.…”

Section: Discussionmentioning

confidence: 99%

Fenofibrate in Primary Biliary Cirrhosis: A Pilot Study

Liberopoulos¹,

Florentin²,

Elisaf³

et al. 2010

TOCMJ

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Background:Most patients with primary biliary cirrhosis (PBC) are treated with ursodeoxycholic acid (UDCA); however, some do not respond fully. PBC is also associated with dyslipidemia, but a link with vascular risk has not been confirmed.Methods and Results:In this study we compared UDCA monotherapy with fenofibrate plus UDCA in PBC patients with incomplete biochemical response to UDCA monotherapy for ≥ 8 months. Ten patients (57.2±13.3 years old) with PBC and persistent elevations of liver enzymes after treatment with UDCA (600 mg/day) were randomized to continue UDCA (4 patients) or to receive micronized fenofibrate (200 mg/day) plus UDCA (6 patients) for 8 weeks. Significant reductions in total cholesterol, triglycerides and non-high density lipoprotein cholesterol were observed in the combination treatment group. The serum activities of alkaline phosphatase, gamma-glutamyl transpeptidase and alanine aminotranferase also decreased in this group compared with baseline (-32.6%; p=0.012, -44%; p=0.031 and -16.9%; p=0.029, respectively). In contrast, no significant alterations in liver enzymes or lipid profile were observed in patients who continued UDCA monotherapy. The changes in the lipid and enzyme variables differed significantly (p<0.03) between the 2 groups. Fenofibrate was well tolerated.Conclusions:The administration of fenofibrate plus UDCA seems to be safe and may improve lipid and liver indices in patients with PBC who do not respond fully to UDCA monotherapy. Whether the improved lipid profile translates into a decreased risk of vascular events remains to be established.

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

Cited by 22 publications

References 49 publications

Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF

Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF

PPARα contributes to colonic protection in mice with DSS-induced colitis

Fenofibrate in Primary Biliary Cirrhosis: A Pilot Study

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