Prostaglandin E2: A potent activator of hyaluronan synthase 1 in type-B-synoviocytes

We demonstrated earlier that the gene HAS1 is inactive in resting type-B-synoviocytes but can be readily activated by a series of proinflammatory cytokines including IL-1β. Here we show that in type-B-synoviocytes mRNA levels for the gene COX-2 increase more than 200-fold in response to IL-1β treatment, whereas COX-1 mRNA levels remain virtually unchanged. We tested a series of eicosanoids and demonstrate that PGE2 is a very potent activator of HAS1 in synoviocytes. While μmol concentrations of PGI2 are required to activate HAS1, low nmol concentrations of PGE2 are sufficient. In addition, while two thromboxane A2 analogs moderately activated HAS1 at higher concentrations, the lipoxygenase pathway product LTB4 was without effect. A series of COX inhibitors blocked IL-1β induced HAS1 activation. Similarly, sodium salicylate (NaSal) also suppressed IL-1β induced HAS1 activation. Furthermore, electrophoretic mobility shift assays and PGE2 ELISA experiments demonstrate that NaSal completely prevents PGE2 release but does not interfere with NF-κB translocation. PGE2 is a very powerful activator of HAS1 transcription and translation. Such data indicate that the effect of IL-1β on HAS1 is mediated by prostaglandins. Additionally, NaSal is a potent suppressor of HAS1 activation. These findings point towards HAS1 as a gene of importance in inflammation.