Transforming growth factor beta1 and laminin-111 cooperate in the induction of interleukin-16 expression in synovial fibroblasts from patients with rheumatoid arthritis.

OBJECTIVES: In synovial tissues of patients with rheumatoid arthritis (RA), strong expression of laminins and integrins co-localises with increased expression of inflammatory cytokines. Synovial fibroblasts (SF) contribute to the pathogenesis of RA through increased expression of cytokines and chemoattractant factors, one of which is interleukin-16 (IL16). A study was undertaken to investigate the regulatory pathways of IL16 in SF from patients with RA (RA-SF) and osteoarthritis (OA-SF). METHODS: SF were seeded in laminin-coated flasks and activated by the addition of cytokines. The expression of IL16 was investigated by quantitative RT-PCR, immunoblotting and ELISA; its biological activity was determined by a cell migration assay. Cell-matrix interactions were investigated by cell binding and attachment assays. Relevant intracellular signalling pathways were studied by immunoblotting and with pharmacological blocking reagents. RESULTS: Stimulation of SF with transforming growth factor beta(1)(TGF-beta(1)) and growth on laminin-111 (LM-111) significantly increased the expression of IL16. Binding to LM-111 induced significantly more IL16 mRNA in RA-SF than in OA-SF (p<0.05). The IL16 cytokine was detected in supernatants of TGF-beta(1)-activated and in LM-111+TGF-beta(1)-activated RA-SF (38 to 62 pg/ml), but not in supernatants of OA-SF. This IL16 regulation involved p38MAPK, ERK1/2 and SMAD2 signalling, but not NFkappaB. CONCLUSIONS: Binding of RA-SF to LM-111 in the presence of TGF-beta(1) triggers a significant IL16 response and thus may contribute to the infiltration of CD4+ lymphocytes into synovial tissues. This mode of IL16 induction represents a novel pathway leading to IL16 production in RA-SF but not in OA-SF, which operates independently of NFkappaB signalling.

EEG coherence and reference signals: experimental results and mathematical explanations.

Coherence has become an essential tool in the description of functional relationships between EEG signals generated within various brain areas. In EEG coherence analysis, the reference signal has an important influence, as an improper reference can distort the results and make them impossible to interpret. In the study, EEG are recorded from one volunteer in 11 sessions, with electrodes selected according to the international 10-20 system against FCz. Additional electrodes are placed on the nose, chin and left and right ear lobes, and recordings are made also against FCz. This enables re-referencing of the stored EEG signals for different reference sites, averaged reference signals, common average reference, Laplacian and bipolar. Coherence values using single reference electrodes depend on the reference site to a large extent. Reliable results are obtained using averaged non-cephalic signals as reference ([A1 + A2]/2). Coherence based on FCz yields slightly lower or higher values than that based on non-cephalic reference sites. Completely different results yield common average reference recordings, Laplacian and bipolar recordings, probably owing to the cancellation effect of essential signal portions using these techniques. A mathematical model for coherence based on signal-to-noise ratios is introduced to explain the experimental findings: the model demonstrates that noisy reference signals lead to coherence increase, whereas a coherent amount in the reference signal leads to coherence decrease.