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TGF-β1 and laminin-111 cooperate in the induction of IL-16 expression in synovial fibroblasts from rheumatoid arthritis patients
  1. Katrin Warstat (katrin.warstat{at}uni-tuebingen.de)
  1. UKT, Germany
    1. Maik Hoberg (maik.hoberg{at}lrz.tu-muenchen.de)
    1. Technical University Munich, Germany
      1. Maximilian Rudert (maximilian.rudert{at}lrz.tu-muenchen.de)
      1. Technical University Munich, Germany
        1. Shanli Tsui (stsui{at}labiomed.org)
        1. Harbor-UCLA Torrance CA, United States
          1. Thomas Pap (thomas.pap{at}uni-muenster.de)
          1. University Munster, Germany
            1. Brigitte Angres (angres{at}nmi.de)
            1. NMI Reutlingen, Germany
              1. Mike Essl (mike.essl{at}uni-tuebingen.de)
              1. UKT, Germany
                1. Terry J Smith (tsmith{at}labiomed.org)
                1. Harbor-UCLA Torrance CA, United States
                  1. William W Cruikshank (bcruiksh{at}bu.edu)
                  1. Boston University, Boston MA, United States
                    1. Gerd Klein (gerd.klein{at}uni-tuebingen.de)
                    1. UKT, Germany
                      1. Steffen Gay (steffen.gay{at}ruz.usz.ch)
                      1. University Hospital Zurich, Switzerland
                        1. Wilhelm K Aicher (aicher{at}uni-tuebingen.de)
                        1. UKT, Germany

                          Abstract

                          Objectives: In synovial tissues of rheumatoid arthritis (RA) patients strong expression of laminins and integrins co-localizes with elevated expression of inflammatory cytokines. Synovial fibroblasts (SF) contribute to the pathogenesis of RA through elevated expression of cytokines and chemoattractant factors, one of which is IL-16. We therefore investigated regulatory pathways of IL-16 in SF from RA and osteoarthritis (OA) patients.

                          Methods: SF were seeded in laminin-coated flasks and activated by the addition of cytokines. Expression of IL-16 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 signaling pathways were studied by immunoblotting and with pharmacological blocking reagents.

                          Results: The stimulation of SF with TGF-β1 and growth on laminin-111 (LM-111) significantly increased the expression of IL-16. In RA-SF, binding to LM-111 induced significantly more IL-16 mRNA than in OA-SF (p<0.05). The IL-16 cytokine was detected in supernatants of TGF-β1-activated and in LM-111 plus TGF-β1-activated RA-SF (38 to 62 pg/ml), but not in supernatants of OA-SF. This IL-16 regulation involved p38MAPK, ERK1/2 and SMAD2 signaling, but not NFκB.

                          Conclusions: Binding of RA-SF to LM-111 in the presence of TGF-β1 triggers a significant IL-16 response and thus may contribute to the infiltration of CD4+ lymphocytes into synovial tissues. This mode of IL-16 induction represents a novel pathway leading to IL-16 production in RA-SF but not in OA-SF, and it operates independently of NFκB signaling.

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