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DBA/1 mice expressing the human TNF-alpha transgene develop a severe, erosive arthritis: characterization of the cytokine cascade and cellular composition.

D M Butler, A M Malfait, L J Mason, P J Warden, G Kollias, R N Maini, M Feldmann and F M Brennan
J Immunol September 15, 1997, 159 (6) 2867-2876;
D M Butler
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A M Malfait
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L J Mason
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P J Warden
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G Kollias
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R N Maini
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M Feldmann
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F M Brennan
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Abstract

Arthritis spontaneously develops in mice expressing a human TNF-alpha transgene modified with the 3' untranslated region of beta-globin. We have backcrossed these mice onto the arthritis-susceptible DBA/1 background and found an acceleration of the onset of arthritis with successive generations of interbreeding. Bioactive TNF-alpha in primary synovial membrane cell cultures was significantly higher in the DBA/1 transgenic mice than in transgenic mice on the original background. Elevated levels of human TNF-alpha were accompanied by increases in synovial cell expression of murine IL-1beta and IL-6, but murine granulocyte-macrophage CSF, IFN-gamma, and IL-4 could not be detected. Interestingly, the anti-inflammatory cytokine IL-10 could be detected, but levels were not modulated by expression of the transgene. Analysis of the synovial membrane cell composition revealed that >50% of synovial cells were CD45-negative cells, presumably fibroblasts and endothelial cells, and the majority of CD45-expressing cells were neutrophils. Peritoneal macrophages and lymphocytes from the spleen, bone marrow, and lymph nodes required LPS stimulation to produce human TNF-alpha, indicating that, when activated, cells of these lineages were capable of expressing the transgene; however, few were found in synovial tissues. In contrast, fibroblasts derived from synovial tissue spontaneously released human TNF-alpha, and using immunohistochemical techniques, this cytokine was localized to fibroblast-like cells and chondrocytes. We propose that arthritis in DBA/1 human TNF-alpha transgenic mice is driven in part through the spontaneous expression of transgene by connective tissue cells, and there is little evidence of the participation of lymphocytes in this model.

  • Copyright © 1997 by American Association of Immunologists

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The Journal of Immunology
Vol. 159, Issue 6
15 Sep 1997
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DBA/1 mice expressing the human TNF-alpha transgene develop a severe, erosive arthritis: characterization of the cytokine cascade and cellular composition.
D M Butler, A M Malfait, L J Mason, P J Warden, G Kollias, R N Maini, M Feldmann, F M Brennan
The Journal of Immunology September 15, 1997, 159 (6) 2867-2876;

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DBA/1 mice expressing the human TNF-alpha transgene develop a severe, erosive arthritis: characterization of the cytokine cascade and cellular composition.
D M Butler, A M Malfait, L J Mason, P J Warden, G Kollias, R N Maini, M Feldmann, F M Brennan
The Journal of Immunology September 15, 1997, 159 (6) 2867-2876;
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Print ISSN 0022-1767        Online ISSN 1550-6606