Maqola

The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles

Jörg H. W. DistlerCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705Astrid JüngelCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705Lars C HuberCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705Christian A. SeemayerCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705Charles F. ReichCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705Renate E. GayCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705Beat A. MichelCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705A. FontanaCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705Steffen GayCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705David S. PisetskyCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705Oliver DistlerCenter of Experimental Rheumatology, Department of Rheumatology, and Section for Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland; Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and Division of Rheumatology, Durham Veterans Affairs Hospital and Duke University Medical Center, Durham, NC 27705

2005en

ABI

Annotatsiya

Rheumatoid arthritis is a chronic inflammatory disease characterized by destruction of cartilage and bone that is mediated by synovial fibroblasts. To determine the mechanisms by which these cells are activated to produce matrix metalloproteinases (MMPs), the effects of microparticles were investigated. Microparticles are small membrane-bound vesicles whose release from immune cells is increased during activation and apoptosis. Because microparticles occur abundantly in the synovial fluid in rheumatoid arthritis, they could represent novel stimulatory agents. Microparticles derived from T cells and monocytes strongly induced the synthesis of MMP-1, MMP-3, MMP-9, and MMP-13 in fibroblasts. The induction was time-dependent, with effects primarily observed after 36 h; under these conditions, MMP-2, MMP-14, and tissue inhibitor of MMP-1 (TIMP-1), TIMP-2, and TIMP-3 were not induced. Microparticles also increased the synthesis of inflammatory mediators including IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), and MCP-2. In Ikappa-B-transfected synovial fibroblasts, MMPs were less inducible by microparticles compared with wild-type fibroblasts. Blocking of TNFalpha and IL-1beta with antibodies against TNFalpha and with IL-1 receptor antagonist did not abrogate stimulation by microparticles. These data provide evidence for a novel mechanism by which vesicles derived from activated or apoptotic immune cells can promote the destructive activity of synovial fibroblasts in rheumatoid arthritis.

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DOI: 10.1073/pnas.0409781102

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