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.