Hyaluronan production in synoviocytes as a consequence of viral infections: HAS1 activation by Epstein-Barr virus and synthetic double- and single-stranded viral RNA analogs.
One of the hallmarks of arthritis is swollen joints containing unusually high quantities of hyaluronan. Intact hyaluronan molecules facilitate cell migration by acting as ligands for CD44. Hyaluronan degradation products, readily formed at sites of inflammation, also fuel inflammatory processes. Irrespective of whether viruses could be a cause of rheumatoid arthritis, there is clear evidence that links viral infections to this debilitating disease. For this study, live Epstein-Barr virus and a number of double- and single-stranded synthetic viral analogs were tested for their effectiveness as activators of hyaluronan (HA) synthesis. As shown herein, Epstein-Barr virus-treated fibroblast-like synoviocytes significantly increase HA production and release. Real time reverse transcription-PCR data show that HAS1 mRNA levels are significantly elevated in virus-treated cells, whereas mRNA levels for the genes HAS2 and HAS3 remain unchanged. As to the mechanism of virus-induced HAS1 transcription, data are presented that imply that among the double- and single-stranded polynucleotides tested, homopolymeric polycytidylic structures are the most potent inducers of HAS1 transcription and HA release, whereas homopolymeric polyinosinic acid is without effect. Analyses of virus-induced signal cascades, utilizing chemical inhibitors of MAPK and overexpressing mutated IKK and IkappaB, revealed that the MAPK p38 as well as the transcription factor NF-kappaB are essential for virus-induced activation of HAS1. The presented data implicate HAS1 as the culprit in unfettered HA release and point out targets in virus-induced signaling pathways that might allow for specific interventions in cases of unwanted and uncontrolled HA synthesis.
Stuhlmeier
Karl M
KM
Ludwig Boltzmann Institute for Rheumatology and Balneology, Kurbadstrasse 10, 1100 Vienna, Austria. karlms@excite.com
D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D011119:Polynucleotides / Q000737:chemistry; D012330:RNA, Double-Stranded / Q000737:chemistry*; D012367:RNA, Viral / Q000737:chemistry*; D013583:Synovial Membrane / Q000166:cytology*; D018800:Thy-1 Antigens / Q000096:biosynthesis; D014777:Virus Diseases / Q000378:metabolism
D016328:NF-kappa B; D009841:Oligonucleotides; D011119:Polynucleotides; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D018800:Thy-1 Antigens; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C523794:HAS1 protein, human; D000076002:Hyaluronan Synthases