Effects of leflunomide on immune responses and models of inflammation

Bartlett, Richard; Anagnostopulos, Hristo; Zielinski, Thomas; Mattar, Thomas; Schleyerbach, R

doi:10.1007/bf00192310

Cited by 75 publications

(43 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whether LPS causes COX-2 or iNOS induction by directly activating tyrosine kinase or indirectly via the release of cytokines remains the subject of investigation. The demonstration that inhibitors of tyrosine kinase suppress the induction of both COX-2 and iNOS provides a possible explanation for the anti-inflammatory activities of such inhibitors in a variety of models (Williams et al, 1992;Levitski, 1992;Bartlett et al, 1993). However, these two enzymes are not expressed in parallel in all models.…”

Section: Discussionmentioning

confidence: 99%

Involvement of tyrosine kinase in the induction of cyclo‐oxygenase and nitric oxide synthase by endotoxin in cultured cells

Akarasereenont

Mitchell

Appleton

et al. 1994

British J Pharmacology

View full text Add to dashboard Cite

1 Cyclo-oxygenase (COX) and nitric oxide synthase (NOS) are two enzymes which have distinct cytokine-inducible isoforms (COX-2 and iNOS). Many cytokine receptors have an intracellular tyrosine kinase domain. Here we have used the tyrosine kinase inhibitors, erbstatin and genistein, to investigate the potential role of tyrosine kinase activation in the induction on COX-2 and iNOS caused by endotoxin (lipopolysaccharide; LPS) in bovine aortic endothelial cells (BAEC) and J774.2 macrophages. 2 The main COX metabolites, 6-oxo-prostaglandin Fl, (6-oxo-PGFI,) (for BAEC) and PGF2, (for 774.2 macrophages) were measured by radioimmunossay: (i) accumulation of COX metabolites from endogenous arachidonic acid was measured at 24 h after addition of LPS (1 jig ml-'); (ii) in experiments designed to measure 'COX activity', COX metabolites generated by BAEC or J774.2 macrophages activated with LPS were assayed (at 12 h after LPS administration) after incubation of the washed cells with exogenous arachidonic acid (30 tiM for 15 min). Western blot analysis with a specific antibody to COX-2 was used to determine the expression of COX-2 protein caused by LPS in cell extracts. Accumulation of nitrite (measured by the Griess reaction) was used as an indicator of NO formation and, hence, iNOS activity. 3 Erbstatin (0.05 to 5 jg ml-') or genistein (0.5 to 50 pg ml-') caused a dose-dependent inhibition of the accumulation of COX metabolites in the supernatant of BAEC or J774.2 macrophages activated with LPS. Erbstatin or genistein also caused a dose-dependent inhibition of 'COX activity' in both cell types. Western blot analysis showed that erbstatin (5 ig ml1') or genistein (50gg ml-') inhibited the expression of COX-2 protein in BAEC and J774.2 macrophages activated with LPS (lLgml-' for 24 h). 4 Erbstatin or genistein also caused a dose-dependent inhibition of nitrite accumulation in J774.2 macrophages activated with LPS (1 sg ml-' for 24 h). In contrast to J774.2 macrophages, BAEC stimulated with LPS (1 pg ml-' for 24 h) did not produce detectable amounts (<1PiM) of nitrite. 5These results suggest that tyrosine phosphorylation is part of the signal transduction mechanism that mediates (i) the induction of COX-2 and iNOS elicited by LPS in J774.2 macrophages, and (ii) the induction of COX-2 by LPS in BAEC.

show abstract

Section: Discussionmentioning

confidence: 99%

Involvement of tyrosine kinase in the induction of cyclo‐oxygenase and nitric oxide synthase by endotoxin in cultured cells

Akarasereenont

Mitchell

Appleton

et al. 1994

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…It is known that leflunomide has a strong anti-inflammatory effect. 18 Manna et al demonstrated that that treatment of human T cells with leflunomide blocks tumor necrosis factor (TNF)-mediated NF-kB activation. 47 NF-kB regulates the expression of many genes that play essential roles in immune and inflammatory responses.…”

confidence: 99%

“…[13][14][15][16][17] In addition to reducing local concentrations of inflammatory mediators, leflunomide also presents antioxidative activity with inhibiting the release of reactive oxygen species from white blood cells. 18 The present study was designed to look at the effect of leflunomide in I/R-induced oxidative stress in the kidneys of rats.…”

Section: Introductionmentioning

confidence: 99%

Prevention of renal ischemia/reperfusion‐induced injury in rats by leflunomide

Karaman

Türkmen²,

Gürsul

et al. 2006

Int J of Urology

View full text Add to dashboard Cite

Objective: There is increasing evidence to suggest that toxic oxygen radicals play an essential role in the pathogenesis of ischemia/ reperfusion (I/R) injury in the kidney. This study was designed to investigate the effects of leflunomide, an isoxazole derivative and a unique immunomodulatory agent, in I/R-induced renal injury in rats. Methods: Forty female Sprague-Dawley rats were divided equally into four groups: (I) control (only leflunomide 10 mg/kg, intragastrically treated); (II) sham operated (only unilateral nephrectomy); (III) I/R; and (IV) leflunomide (10 mg/kg for two doses prior to experiment) plus I/R groups. In groups III and IV, after unilateral nephrectomy, the rats were subjected to 60 min of left renal pedicle occlusion, followed by 6 h of reperfusion. At the end of the reperfusion period, rats were killed and kidneys and blood were removed. Catalase, myeloperoxidase and xanthine oxidase activities, and malondialdehyde, nitric oxide and protein carbonyl levels were determined in renal tissue. Serum creatinine, blood urea nitrogen and aspartate aminotransferase were measured for the evaluation of renal function. In histopathological examination, renal damage was scored 0-3. Results: Group III animals demonstrated severe deterioration of renal function, renal morphology and a significant renal oxidative stress. Pretreatment of animals with leflunomide markedly attenuated renal dysfunction, morphological alterations, reduced elevated oxidative stress products levels and restored the depleted renal antioxidant enzyme. Conclusion:The findings imply that oxygen radicals play a causal role in I/R-induced renal injury, and leflunomide exerts renoprotective effects probably by the radical scavenging and antioxidant activities with immunomodulatory effect.

show abstract

“…Activated CD4ϩ T cells proliferate rapidly during the progression of RA, a process involving de novo pyrimidine synthesis (5). Leflunomide acts to inhibit T cell proliferation by preventing pyrimidine generation and subsequent DNA synthesis (6)(7)(8).…”

mentioning

confidence: 99%

The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: A five‐year followup study

Kalden¹,

Schattenkirchner²,

Sörensen³

et al. 2003

Arthritis & Rheumatism

117

View full text Add to dashboard Cite

Results. A total of 214 patients (mean age 57 years) were treated with leflunomide for >2 years; 74.8% of the patients were female. The mean disease duration was 4.1 years (range 0.1-26.6 years), and in 44% of patients, RA was first diagnosed within 2 years of entry into the phase III studies. The mean duration of leflunomide treatment was 4.6 years (range 2.8-5.8 years), and 32% of patients had received no previous treatment with disease-modifying antirheumatic drugs. ACR20, ACR50, and ACR70 response rates and HAQ scores at 1 year were maintained through year 4 or until the end point. No new types of adverse events were observed, and liver function was normal at baseline and at the end point in the majority of patients.Conclusion. The improvements in both functional ability and physician-based efficacy measures seen with leflunomide after 1 year were maintained for up to 5 years (maximum treatment duration 5.8 years), demonstrating that the early efficacy of leflunomide in patients with RA is sustained long-term, and that the long-term safety profile of leflunomide is no different from that observed in phase III trials.

show abstract

Effects of leflunomide on immune responses and models of inflammation

Cited by 75 publications

References 26 publications

Involvement of tyrosine kinase in the induction of cyclo‐oxygenase and nitric oxide synthase by endotoxin in cultured cells

Involvement of tyrosine kinase in the induction of cyclo‐oxygenase and nitric oxide synthase by endotoxin in cultured cells

Prevention of renal ischemia/reperfusion‐induced injury in rats by leflunomide

The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: A five‐year followup study

Contact Info

Product

Resources

About