Expression of hyaluronan synthase messenger ribonucleic acids and their induction by interleukin-1 beta in human orbital fibroblasts: Potential insight into the molecular pathogenesis of thyroid-associated ophthalmopathy

The disordered accumulation of hyaluronan; a nonsulfated glycosaminoglycan, is a hallmark feature of the tissue remodeling observed in thyroid-associa ted ophthalmopathy (TAO). Orbital fibroblasts have been shown to exhibit su bstantial up-regulation of hyaluronan synthesis when activated with proinfl ammatory cytokines such as interleukin-1 beta (IL-1 beta). Recently, three members of the hyaluronan synthase (HAS) gene family were cloned. Here we r eport that IL-1 beta can dramatically and consistently induce in orbital fi broblasts the expression of HAS2 in the five orbital strains examined. HAS3 messenger ribonucleic acid (mRNA) was also detectable in all these strains by RT-PCR under both control and IL-1 beta-treated conditions. In contrast , HAS1 mRNA was detected by Northern blot analysis in only one of the strai ns treated with IL-1 beta, but in three of five strains examined by RT-PCR. These HAS inductions by the cytokine were time dependent and could be atte nuated with dexamethasone and cycIoherdmide. They were accompanied by an in creased incorporation of [H-3]glucosamine into hyaluronan, and dexamethason e could attenuate induction of macromolecular synthesis as well. Our observ ations suggest that the cytokine-dependent induction of the HAS genes in or bital fibroblasts may be the molecular basis at least in part for the incre ased accumulation of hyaluronan, driven by immunocompetent cells, in orbita l connective tissue and the extraocular muscles in TAO.