Inhibition of tumor necrosis factor α–induced prostaglandin E2 production by the antiinflammatory cytokines interleukin-4, interleukin-10, and interleukin-13 in osteoarthritic synovial fibroblasts: Distinct targeting in the signaling pathways
✍ Scribed by Nada Alaaeddine; John A. Di Battista; Jean-Pierre Pelletier; Kayghobad Kiansa; Jean-Marie Cloutier; Johanne Martel-Pelletier
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 368 KB
- Volume
- 42
- Category
- Article
- ISSN
- 0004-3591
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✦ Synopsis
Objective:
To investigate the effects of the antiinflammatory cytokines interleukin-4 (il-4), il-10, and il-13 on tumor necrosis factor alpha (tnfalpha)-induced prostaglandin e2 (pge2) release in the cellular signaling cascade on human osteoarthritis (oa) synovial fibroblasts.
Methods:
Human oa synovial fibroblasts were cultured to explore the impact of il-4, il-10, and il-13 on tnfalpha binding to tnf receptors (tnfr), soluble tnfr (stnfr), cytoplasmic phospholipase a2 (cpla2), and cyclooxygenase-2 (cox-2) production, and on the binding activity of the transcription factors nuclear factor kappab (nf-kappab), ccaat-enhancer binding protein (c/ebp), activator protein 2 (ap-2), and cyclic amp response element-binding protein (creb).
Results:
Il-4, il-10, and il-13 at 5 ng/ml dramatically reduced tnfalpha-induced pge2 release by approximately 90% (p < 0.0001). il-4 up-regulated the level of tnfalpha-induced tnfr by 47% (p < 0.06), while il-10 down-regulated it by 71% (p < 0.02); il-13 had no effect. although statistical significance was not reached, all 3 cytokines up-regulated the basal level of stnfr-55. il-4 and il-10, while not altering the basal level of stnfr-75, significantly increased the tnfalpha-stimulated release of stnfr-75. il-4, il-10, and il-13 reduced the tnfalpha-induced cox-2 level, and il-4 and il-10 reduced the cpla2 level. il-4 had no effect on tnfalpha up-regulation of nf-kappab, and a slight decrease was noted with il-10 and il-13 at the highest concentration used (5 ng/ml). il-4 and il-13 decreased the tnfa-induced c/ebp accumulation in a dose-dependent manner, while il-10 up-regulated its basal level. ap-2 and creb were not induced by tnfalpha.
Conclusion:
The results indicate that these antiinflammatory cytokines reversed the tnfalpha-induced release of pge2 by oa synovial fibroblasts, by acting at various levels of the tnfa-dependent signaling cascade. these data shed new light on the mechanisms by which these cytokines reduce inflammatory processes.