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Therapeutic Targeting of IL-6 Trans Signaling Counteracts STAT3 Control of Experimental Inflammatory Arthritis

Mari A. Nowell, Anwen S. Williams, Sarah A. Carty, Jürgen Scheller, Anthony J. Hayes, Gareth W. Jones, Peter J. Richards, Simon Slinn, Matthias Ernst, Brendan J. Jenkins, Nicholas Topley, Stefan Rose-John and Simon A. Jones
J Immunol January 1, 2009, 182 (1) 613-622; DOI: https://doi.org/10.4049/jimmunol.182.1.613
Mari A. Nowell
*Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom;
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Anwen S. Williams
†Department of Rheumatology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom;
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Sarah A. Carty
†Department of Rheumatology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom;
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Jürgen Scheller
‡Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany;
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Anthony J. Hayes
§Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, United Kingdom;
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Gareth W. Jones
*Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom;
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Peter J. Richards
*Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom;
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Simon Slinn
†Department of Rheumatology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom;
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Matthias Ernst
¶Ludwig Cancer Research Institute, Melbourne, Victoria, Australia; and
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Brendan J. Jenkins
∥Monash Institute for Medical Research, Clayton, Victoria, Australia
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Nicholas Topley
*Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom;
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Stefan Rose-John
‡Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany;
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Simon A. Jones
*Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom;
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Abstract

Cytokine control of the synovial infiltrate is a central process in the development of inflammatory arthritis. In this study, we combine genetic approaches and intervention strategies to describe a fundamental requirement for IL-6-mediated STAT3 signaling in orchestrating the inflammatory infiltrate in monoarticular and systemic models of experimental arthritis. STAT3 activation via the common gp130 signal-transducing receptor for all IL-6-related cytokines led to increased retention of neutrophils and T cells within the inflamed synovium, which included STAT3-regulated IL-17A-secreting T cells. Control of leukocyte infiltration was reliant upon IL-6 signaling via its soluble receptor (termed IL-6 trans signaling), as evidenced by selective blockade of this alternative IL-6 signaling pathway using an engineered variant of soluble gp130 (sgp130Fc). This therapeutic intervention led to substantial clinical improvement in mice with emerging or established incidence of systemic arthritis. These data illustrate that IL-6 control of STAT3 is critical for regulating the synovial infiltrate in inflammatory arthritis, and suggest that selective inhibition of IL-6 trans signaling may provide a more refined intervention strategy for blocking IL-6-driven proarthritic activities.

  • Received August 11, 2008.
  • Accepted October 21, 2008.
  • Copyright © 2009 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 182 (1)
The Journal of Immunology
Vol. 182, Issue 1
1 Jan 2009
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Therapeutic Targeting of IL-6 Trans Signaling Counteracts STAT3 Control of Experimental Inflammatory Arthritis
Mari A. Nowell, Anwen S. Williams, Sarah A. Carty, Jürgen Scheller, Anthony J. Hayes, Gareth W. Jones, Peter J. Richards, Simon Slinn, Matthias Ernst, Brendan J. Jenkins, Nicholas Topley, Stefan Rose-John, Simon A. Jones
The Journal of Immunology January 1, 2009, 182 (1) 613-622; DOI: 10.4049/jimmunol.182.1.613

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Therapeutic Targeting of IL-6 Trans Signaling Counteracts STAT3 Control of Experimental Inflammatory Arthritis
Mari A. Nowell, Anwen S. Williams, Sarah A. Carty, Jürgen Scheller, Anthony J. Hayes, Gareth W. Jones, Peter J. Richards, Simon Slinn, Matthias Ernst, Brendan J. Jenkins, Nicholas Topley, Stefan Rose-John, Simon A. Jones
The Journal of Immunology January 1, 2009, 182 (1) 613-622; DOI: 10.4049/jimmunol.182.1.613
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