The Active form of Leflunomide, HMR1726, Facilitates TNF-a and IL-17 Induced MMP-1 and MMP-3 Expression

Alexander, Dorothea; Friedrich, Björn; Abruzzese, Tanja; Gondolph-Zink, B.; Wülker, Nikolaus; Aicher, Wilhelm K.

doi:10.1159/000091465

Cited by 11 publications

(7 citation statements)

References 29 publications

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“…Stronger effect of T-614 on the invasiveness and MMPs production of RA FLS after stimulation of IL-17A hinted it could be a commendable choice for RA patients during early stage. Some other disease-modifying antirheumatic drugs (DMARD), such as leflunomide, were not able to abolish expression of MMP in synoviocytes activated with TNF-α and IL-17, so the inhibition by T-614 could be important in the treatment of rheumatoid arthritis [28].…”

Section: Discussionmentioning

confidence: 99%

T-614 alters the production of matrix metalloproteinases (MMP-1 andMMP-3) and inhibits the migratory expansion of rheumatoid synovial fibroblasts, in vitro

Teng

et al. 2012

International Immunopharmacology

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Section: Discussionmentioning

confidence: 99%

T-614 alters the production of matrix metalloproteinases (MMP-1 andMMP-3) and inhibits the migratory expansion of rheumatoid synovial fibroblasts, in vitro

Teng

et al. 2012

International Immunopharmacology

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“…To further explore the regulation of mPGES-1 and related PGE 2 -synthesizing enzymes in gingival fibroblasts, we here used a global gene expression profiling approach to achieve a broader view of the genes and signal pathways related to the regulation of mPGES-1, in parallel with COX-2, using microarray analysis of TNFα-treated gingival fibroblasts. The effect of TNFα on global gene expression profiles has previously been investigated in synovial fibroblasts, preosteoblasts and HeLa cells, but not in gingival cells [52-56]. With regard to periodontal disease, microarray analysis of gingival tissue has been used in an attempt to define subclasses of periodontitis and to evaluate the effect of periodontal therapy [57,58].…”

Section: Discussionmentioning

confidence: 99%

Signal pathways JNK and NF-κB, identified by global gene expression profiling, are involved in regulation of TNFα-induced mPGES-1 and COX-2 expression in gingival fibroblasts

et al. 2010

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BackgroundProstaglandin E2 (PGE2) is involved in several chronic inflammatory diseases including periodontitis, which causes loss of the gingival tissue and alveolar bone supporting the teeth. We have previously shown that tumor necrosis factor α (TNFα) induces PGE2 synthesis in gingival fibroblasts. In this study we aimed to investigate the global gene expression profile of TNFα-stimulated primary human gingival fibroblasts, focusing on signal pathways related to the PGE2-synthesizing enzymes prostaglandin E synthases (PGES), as well as the upstream enzyme cyclooxygenase-2 (COX-2) and PGE2 production.ResultsMicroarray and western blot analyses showed that the mRNA and protein expression of the inflammatory induced microsomal prostaglandin E synthase-1 (mPGES-1) was up-regulated by the cytokine TNFα, accompanied by enhanced expression of COX-2 and increased production of PGE2. In contrast, the expression of the isoenzymes microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNFα treatment. Using oligonucleotide microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, differentially expressed genes in response to TNFα treatment were identified. Enrichment analysis of microarray data indicated two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-κB (NF-κB). To evaluate their involvement in the regulation of mPGES-1 and COX-2 expression, we used specific inhibitors as well as phosphorylation analysis. Phosphorylation analysis of JNK (T183/Y185) and NF-κB p65 (S536) showed increased phosphorylation in response to TNFα treatment, which was decreased by specific inhibitors of JNK (SP600125) and NF-κB (Bay 11-7082, Ro 106-9920). Inhibitors of JNK and NF-κB also decreased the TNFα-stimulated up-regulation of mPGES-1 and COX-2 as well as PGE2 production.ConclusionIn the global gene expression profile, the enrichment analysis of microarray data identified the two signal transduction pathways JNK and NF-κB as positively regulated by the cytokine TNFα. Inhibition of these TNFα-activated signal pathways reduced the expression of mPGES-1 and COX-2 as well as their end product PGE2 in gingival fibroblasts. The involvement of the signal pathways JNK and NF-κB in the regulation of PGE2 induced by TNFα may suggest these two pathways as possible attractive targets in the chronic inflammatory disease periodontitis.

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“…Although little is known of TNF induced mast cell signalling some previous reports may support our current findings. TNF has been reported to induce CCL2 transcription through B-Raf/MEK/ERK signaling pathways in nasal polyp fibroblasts [41], and to stimulate gene expression of MMP-1 and -3 via p38 and MEK1/2 signaling pathways in synoviocytes [42]. TNF can also induce phosphorylation of Akt in cultured human fibroblast-like synoviocytes [43].…”

Section: Discussionmentioning

confidence: 99%

TNF Increases Expression of IL-4 and PARs in Mast Cells

Zhang

Yang²,

He³

2010

Cell Physiol Biochem

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Tumor necrosis factor (TNF) is a proinflammatory cytokine which has been shown to be actively involved in the pathogenesis of allergic inflammation. However, little is known of the effects of TNF on cytokine secretion and protease activated receptor (PAR) expression in mast cells. In the present study, we examined potential influence of TNF on IL-4 and IL-12 release from P815 cells and PAR expression in P815 cells by using flow cytometry analysis, quantitative real time PCR, ELISA and cellular activation of signaling ELISA (CASE) techniques. The results showed that TNF induced up to 2.7-fold increase in IL-4, but not IL-12 release from P815 cells, and PAR-2 antagonist peptide FSLLRY-NH₂ and PAR-4 antagonist peptide trans-cinnamoyl (tc)-YPGKF-NH₂ did not affect TNF induced IL-4 release. Approximately up to 2.4 and 2.3 fold increases in expression of PAR-2 and PAR-4 were observed when cells were incubated with TNF. Pretreatment of cells with TNF for 60 min enhanced trypsin and tryptase induced PAR-2 expression by 2.4 and 2.3 fold; PAR-3 expression by 1.6 and 1.7 fold and PAR-4 expression by 1.6 and 1.7 fold, respectively. LY294002, an inhibitor PI3K abolished TNF induced IL-4 release and phosphorylation of Akt in P815 cells, indicating Akt cell signalling pathway is involved in the event. In conclusion, TNF can stimulate IL-4 release from mast cells through an Akt cell signalling pathway dependent, but PAR independent mechanism. TNF may serve as a regulator for IL-4 production and PAR expression, and through which participates in the mast cell related inflammation.

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The Active form of Leflunomide, HMR1726, Facilitates TNF-a and IL-17 Induced MMP-1 and MMP-3 Expression

Cited by 11 publications

References 29 publications

T-614 alters the production of matrix metalloproteinases (MMP-1 andMMP-3) and inhibits the migratory expansion of rheumatoid synovial fibroblasts, in vitro

T-614 alters the production of matrix metalloproteinases (MMP-1 andMMP-3) and inhibits the migratory expansion of rheumatoid synovial fibroblasts, in vitro

Signal pathways JNK and NF-κB, identified by global gene expression profiling, are involved in regulation of TNFα-induced mPGES-1 and COX-2 expression in gingival fibroblasts

TNF Increases Expression of IL-4 and PARs in Mast Cells

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