NF-kappaB and the MAP kinases/AP-1 pathways are both involved in interleukin-6 and interleukin-8 expression in fibroblast-like synoviocytes stimulated by protein I/II, a modulin from oral streptococci.
As in rheumatoid arthritis (RA), it was demonstrated recently that bacterial fragments of DNA or rRNA are present in the joint and therefore could play a role in inducing or perpetuating the disease, this work was initiated to define mechanisms that account for the stimulatory activities of the oral streptococcal modulin, protein I/II, on fibroblast-like synoviocytes (FLSs) from RA patients. FLSs from RA patients were stimulated with protein I/II, and expression of interleukin (IL)-6 and IL-8 mRNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Immunoblotting by antibodies specific for activated forms of MAPKs and electrophoretic mobility shift assays (EMSAs) were performed to study downstream signalling, which allowed the synthesis of IL-6 and IL-8. We reported that protein I/II interactions with FLSs from RA patients trigger the synthesis and release of IL-6 and IL-8. We also demonstrated that protein I/II enhances the phosphorylation of ERK 1/2, p38 and JNKs and that ERK 1/2 and JNK MAPKs seem to play a more important role than p38 in protein I/II-mediated synthesis of IL-6 and IL-8. Our experiments also indicated that stimulation of FLSs with protein I/II induces nuclear translocation of NF-kappaB, AP-1-binding activity and that NF-kappaB plays a major role in IL-6 and IL-8 secretion from activated cells.
Neff
L
L
Laboratoire d'Immunologie et Biochimie Bactérienne, Inserm U392, Université Louis Pasteur de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400 Illkirch, France.
Zeisel
M
M
Sibilia
J
J
Schöller-Guinard
M
M
Klein
J P
JP
Wachsmann
D
D
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D047310:Apigenin; D001172:Arthritis, Rheumatoid / Q000382:microbiology / Q000503:physiopathology; D001426:Bacterial Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008562:Membrane Glycoproteins; D016328:NF-kappa B / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013291:Streptococcus / Q000502:physiology*; D012460:Sulfasalazine / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D015850:Interleukin-6; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011725:Pyridines; C055764:S-layer proteins; D012460:Sulfasalazine; D047310:Apigenin; D003474:Curcumin; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one