The NF-κB inhibitor pyrrolidine dithiocarbamate blocks IL-1β induced hyaluronan synthase 1 (HAS1) mRNA transcription, pointing at NF-κB dependence of the gene HAS1

The glycosaminoglycan hyaluronan is not merely the simple space filling substance it was long thought to be but is instead being increasingly recognized as a key player in numerous biological processes ranging from embryogenesis to the process of aging. Alterations in hyaluronan syntheses play an important role in ailments associated with aging such as rheumatoid arthritis, atherosclerosis and many forms of cancers, e.g. prostate cancers that mostly affect the elderly. Despite the increasing recognition of hyaluronan as a critical player in many disorders, little is known about the intracellular mechanisms involved in the regulation of the genes encoding hyaluronan synthases (HAS). Herein, evidence is provided that in type-B synoviocytes (TBS) HAS1 is a gene that depends on the transcription factor nuclear factor kappa B (NF-κB) for its activation. Stimulating such cells with IL-1β results in a dose and time dependent activation of HAS1. Pyrrolidine dithiocarbamate (PDTC) blocks IL-1β induced HAS1 activation entirely. Furthermore, PDTC treatment also prevents the degradation of the IκBα in TBS as shown by Western blot experiments. EMSA data confirm that PDCT, at concentrations sufficient to completely block IL-1β induced HAS1 transcription, also entirely blocks IL-1β induced NF-κB translocation. The reported findings stress important differences among the genes encoding hyaluronan and point at a role of HAS1 in inflammatory processes.