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Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice
R J Griffiths1, M A Smith, M L Roach
1Department of Cancer, Immunology, and Infectious Diseases, Pfizer, Inc., Groton, Connecticut 06340, USA.
Abstract:
Collagen-induced arthritis in the DBA/1 mouse is an experimental model of human rheumatoid arthritis. To examine the role of leukotrienes in the pathogenesis of this disease, we have developed embryonic stem (ES) cells from this mouse strain. Here, we report that DBA/1 mice made deficient in 5-lipoxygenase-activating protein (FLAP) by gene targeting in ES cells develop and grow normally. Zymosan-stimulated leukotriene production in the peritoneal cavity of these mice is undetectable, whereas they produce substantial amounts of prostaglandins. The inflammatory response to zymosan is reduced in FLAP-deficient mice. The severity of collagen-induced arthritis in the FLAP-deficient mice was substantially reduced when compared with wild-type or heterozygous animals. This was not due to an immunosuppressive effect, because anti-collagen antibody levels were similar in wild-type and FLAP-deficient mice. These data demonstrate that leukotrienes play an essential role in both the acute and chronic inflammatory response in mice.
Insights
Leukotrienes significantly contribute to inflammation in rheumatoid arthritis models. Mice lacking 5-lipoxygenase-activating protein (FLAP) showed reduced arthritis severity, indicating leukotrienes are crucial for inflammatory responses.
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Collagen-induced arthritis (CIA) in DBA/1 mice serves as a model for human rheumatoid arthritis.
- Leukotrienes are implicated in the pathogenesis of inflammatory diseases.
Purpose of the Study:
- To investigate the role of leukotrienes in CIA pathogenesis.
- To generate and study mice deficient in 5-lipoxygenase-activating protein (FLAP) using gene targeting in embryonic stem (ES) cells.
Main Methods:
- Gene targeting in DBA/1 mouse ES cells to create FLAP-deficient mice.
- Assessment of zymosan-stimulated leukotriene and prostaglandin production.
- Evaluation of inflammatory response to zymosan.
- Induction and assessment of collagen-induced arthritis severity.
- Measurement of anti-collagen antibody levels.
Main Results:
- FLAP-deficient mice developed normally and showed undetectable zymosan-stimulated leukotriene production, but normal prostaglandin production.
- The inflammatory response to zymosan was reduced in FLAP-deficient mice.
- CIA severity was substantially reduced in FLAP-deficient mice compared to wild-type or heterozygous littermates.
- Anti-collagen antibody levels were similar across genotypes, ruling out immunosuppression.
Conclusions:
- Leukotrienes play a critical role in the pathogenesis of collagen-induced arthritis.
- FLAP deficiency significantly ameliorates arthritis severity in a mouse model.
- Leukotrienes are essential mediators of both acute and chronic inflammatory responses in vivo.