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A proinflammatory role for Fas in joints of mice with collagen-induced arthritis

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Abstract

Collagen-induced arthritis (CIA) is a chronic inflammatory disease bearing all the hallmarks of rheumatoid arthritis, e.g. polyarthritis, synovitis, and subsequent cartilage/bone erosions. One feature of the disease contributing to joint damage is synovial hyperplasia. The factors responsible for the hyperplasia are unknown; however, an imbalance between rates of cell proliferation and cell death (apoptosis) has been suggested. To evaluate the role of a major pathway of cell death – Fas (CD95)/FasL – in the pathogenesis of CIA, DBA/1J mice with a mutation of the Fas gene (lpr) were generated. The susceptibility of the mutant DBA-lpr/lpr mice to arthritis induced by collagen type II was evaluated. Contrary to expectations, the DBA-lpr/lpr mice developed significantly milder disease than the control littermates. The incidence of disease was also significantly lower in the lpr/lpr mice than in the controls (40% versus 81%; P < 0.05). However DBA-lpr/lpr mice mounted a robust immune response to collagen, and the expression of local proinflammatory cytokines such as, e.g., tumor necrosis factor α (TNF-α) and IL-6 were increased at the onset of disease. Since the contribution of synovial fibroblasts to inflammation and joint destruction is crucial, the potential activating effect of Fas on mouse fibroblast cell line NIH3T3 was investigated. On treatment with anti-Fas in vitro, the cell death of NIH3T3 fibroblasts was reduced and the expression of proinflammatory cytokines TNF-α and IL-6 was increased. These findings suggest that impairment of immune tolerance by increased T-cell reactivity does not lead to enhanced susceptibility to CIA and point to a role of Fas in joint destruction.

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Abbreviations

AICD:

activation-induced cell death

CFA:

complete Freund's adjuvant

CIA:

collagen-induced arthritis

ConA:

concanavalin A

ELISA:

enzyme-linked immunosorbent assay

Fab:

antigen-binding fragment

FACS:

fluorescence-activated cell sorter

FasL:

Fas ligand

FITC:

fluorescein isothiocyanate

IFN:

interferon

IL:

interleukin

mAb:

monoclonal antibody

PBS:

phosphate-buffered saline

PCR:

polymerase chain reaction

PE:

phycoerythrin

RA:

rheumatoid arthritis

RPMI:

Roswell Park Memorial Institute [medium]

TNF:

tumor necrosis factor.

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Acknowledgements

The authors would like to thank Ms Ilona Klamfuss and Ms Eva Lorbeer for excellent technical assistance. This work is supported by grant IB24/3-2 from the DFG (German Research Foundation) and FKZ 01ZZ0108 from the BMBF (Federal Ministry for Research) to SMI.

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Authors and Affiliations

  1. Department of Immunology, University of Rostock, Rostock, Germany

    Hoang Tu-Rapp, André Hammermüller, Hansjürgen Köhler, Hans-Jürgen Thiesen & Saleh M Ibrahim

  2. Department of Neurology, University of Rostock, Rostock, Germany

    Eilhard Mix

  3. Department of Pathology, University of Rostock, Rostock, Germany

    Hans-Jürgen Kreutzer & Horst Nizze

  4. Institute of Biology VII, RWTH Aachen, Aachen, Germany

    Roland Goerlich

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  1. Hoang Tu-Rapp
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  2. André Hammermüller
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Correspondence to Hoang Tu-Rapp.

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Tu-Rapp, H., Hammermüller, A., Mix, E. et al. A proinflammatory role for Fas in joints of mice with collagen-induced arthritis. Arthritis Res Ther 6, R404 (2004). https://doi.org/10.1186/ar1205

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