title: Impaired release of IL-18 from fibroblast-like synoviocytes activated with protein I/II, a pathogen-associated molecular pattern from oral streptococci, results from defective translation of IL-18 mRNA in pro-IL-18.
abstract: Proinflammatory cytokines such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-18 are key mediators of joint inflammation during rheumatoid arthritis (RA). This chronic inflammation may result from a non-specific innate immune response that could be triggered by a wide variety of microorganisms, because numerous bacterial fragments have been identified in the joints of RA patients. As we have demonstrated previously that protein I/II, a pathogen-associated molecular pattern (PAMP) from oral streptococci, triggers IL-6 and IL-8 gene expression and release from either THP-1 cells or fibroblast-like synoviocytes (FLSs), we next explored the capacity of protein I/II to induce the synthesis and release of IL-18 in THP-1 cells and in FLSs isolated from either RA or osteoarthritis (OA) patients. We demonstrate that protein I/II induced IL-18 mRNA in both THP-1 cells and FLSs but, in contrast to THP-1 cells, gene expression was not associated with the synthesis of the corresponding protein in FLSs. Furthermore, our studies revealed that FLSs did not express the biologically inactive precursor, pro-IL-18, in response to protein I/II. Using actinomycin D, we also showed that IL-18 mRNA is unstable in FLSs. Taken together, these data indicate that lack of IL-18 release from activated FLSs results from a defect in translation of IL-18 mRNA into pro-IL-18 because of rapid degradation of IL-18 mRNA.
authors.affiliation: Inserm 392, Infection et Inflammation, Université Louis Pasteur de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400 Illkirch, France.
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Neff
authors.forename: John
authors.initials: J
authors.lastname: Randle
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Klein
authors.forename: Jean
authors.initials: J
authors.lastname: Sibilia
authors.forename: Dominique
authors.initials: D
authors.lastname: Wachsmann
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D001426:Bacterial Proteins / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D005347:Fibroblasts / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010003:Osteoarthritis / Q000276:immunology / Q000473:pathology; D014176:Protein Biosynthesis; D020871:RNA Stability; D012333:RNA, Messenger / Q000032:analysis / Q000302:isolation & purification; D013295:Streptococcus mutans / Q000472:pathogenicity*; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology*; D014158:Transcription, Genetic
chemical_list: D001426:Bacterial Proteins; D020382:Interleukin-18; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D003609:Dactinomycin