Effects of Leflunomide on Hyaluronan Synthases (HAS): NF-κB-Independent Suppression of IL-1-Induced HAS1 Transcription by Leflunomide

摘要: Despite evidence that points to unfettered hyaluronic acid (HA) production as a culprit in the progression of rheumatic disorders, little is known about differences regulation and biological functions three hyaluronan synthase (HAS) genes. Testing effects drugs with proven anti-inflammatory could help clarify these In this study, we demonstrate leflunomide suppresses HA release fibroblast-like synoviocytes (FLS) dose-dependent manner. We further activity, determined by (14)C-glucuronic incorporation assays. Additional experiments revealed FLS, specifically blocked induction HAS1. HAS2 HAS3, genes are, contrast HAS1, constitutively expressed are not significantly affected. Leflunomide can function NF-kappaB inhibitor. However, EMSA at concentrations used, neither interferes IL-1beta- nor PMA-induced translocation. Furthermore, reconstituting pyrimidine pathway did lead restoration IL-1beta-induced HAS1 activation. More importantly, two tyrosine kinase inhibitors mimicked effect both activation without affecting or HAS3. These data point possible cause for rheumatoid arthritis might explain, least part, beneficial treatment. findings also support concept depends on kinases, indicate blocks suppressing kinases rather than through inhibition