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Transforming growth factor β1 and laminin-111 cooperate in the induction of interleukin-16 expression in synovial fibroblasts from patients with rheumatoid arthritis
  1. K Warstat1,
  2. M Hoberg2,
  3. M Rudert2,
  4. S Tsui3,
  5. T Pap4,
  6. B Angres5,
  7. M Essl6,
  8. T J Smith3,
  9. W W Cruikshank7,
  10. G Klein6,
  11. S Gay8,
  12. W K Aicher1
  1. 1
    Center for Regenerative Medicine and Department of Orthopaedic Surgery, Center for Medical Research, Tübingen, Germany
  2. 2
    Department of Orthopaedic Surgery, Technical University, Munich, Germany
  3. 3
    Department of Medicine, Harbor-UCLA Medical Center, Torrance, California, USA
  4. 4
    Division of Molecular Medicine of Musculoskeletal Tissue, University Hospital, Münster, Germany
  5. 5
    NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
  6. 6
    Section for Transplantation Immunology and Immunohematology, Center for Medical Research, Tübingen, Germany
  7. 7
    Pulmonary Center, Boston University Medical Center, Boston, Massachusetts, USA
  8. 8
    Department of Rheumatology, University Hospital, Zürich, Switzerland
  1. Correspondence to Dr W K Aicher, ZMF Research Laboratories, Center for Regenerative Medicine and Department of Orthopaedic Surgery, University of Tübingen Medical School, Waldhoernle Strasse 22, D 72072 Tübingen, Germany; aicher{at}


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 β1 (TGF-β1) 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-β1-activated and in LM-111+TGF-β1-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 NFκB.

Conclusions: Binding of RA-SF to LM-111 in the presence of TGF-β1 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 NFκB signalling.

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  • ▸ Additional data are published online only at

  • Funding This project was supported by DFG grants to WKA (Ai-16/10, -16/14, -16/19) and TP (DFG SFB492 TP19), by NIH grants to TJS (EY08976, EY11708 and DK063121) and in part by institutional funding.

  • Competing interests None.

  • Ethics approval This study was approved by the local ethics committee.

  • Provenance and Peer review Not commissioned; externally peer reviewed.

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