title: The NF-kappaB inhibitor pyrrolidine dithiocarbamate blocks IL-1beta induced hyaluronan synthase 1 (HAS1) mRNA transcription, pointing at NF-kappaB dependence of the gene HAS1.
abstract: 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-kappaB) for its activation. Stimulating such cells with IL-1beta results in a dose and time dependent activation of HAS1. Pyrrolidine dithiocarbamate (PDTC) blocks IL-1beta induced HAS1 activation entirely. Furthermore, PDTC treatment also prevents the degradation of the IkappaBalpha in TBS as shown by Western blot experiments. EMSA data confirm that PDCT, at concentrations sufficient to completely block IL-1beta induced HAS1 transcription, also entirely blocks IL-1beta induced NF-kappaB translocation. The reported findings stress important differences among the genes encoding hyaluronan and point at a role of HAS1 in inflammatory processes.
authors.affiliation: School of Nursing and Dental Hygiene, Kula Hospital and Clinic, University of Hawaii, 100 Keokea place, Kula, HI 96790, USA. jkao@hhsc.org
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Kao
mesh_terms: D000375:Aging / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000076002:Hyaluronan Synthases; D053583:Interleukin-1beta / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D013859:Thiocarbamates / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases