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Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice.

Griffiths RJ, Smith MA, Roach ML, Stock JL, Stam EJ, Milici AJ, Scampoli DN, Eskra JD, Byrum RS, Koller BH, McNeish JD - J. Exp. Med. (1997)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department 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.

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Collagen-induced arthritis in FLAP deficient mice. DBA/1  mice were immunized with chick type II collagen on day 0 and 21. IL-1  was administered subcutaneously on days 45 and 46 to trigger an arthritic  flare. Disease severity was scored by observation of the paws for redness  and swelling. Open circles, +/+ mice; closed triangles, +/− mice; open  squares, −/− mice. Results are mean ± SEM, n = 3 experiments.
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Figure 2: Collagen-induced arthritis in FLAP deficient mice. DBA/1 mice were immunized with chick type II collagen on day 0 and 21. IL-1 was administered subcutaneously on days 45 and 46 to trigger an arthritic flare. Disease severity was scored by observation of the paws for redness and swelling. Open circles, +/+ mice; closed triangles, +/− mice; open squares, −/− mice. Results are mean ± SEM, n = 3 experiments.

Mentions: The severity of collagen-induced arthritis in the FLAPdeficient mice was reduced at all time points compared with wild-type animals (Fig. 2). The total disease score from days 21–56 (Fig. 2, area under the curve) was reduced by a mean of 73%, P <0.001 (Table 2). Heterozygous animals had a smaller, but significant decrease also, mean of 37%, P <0.05. The reduced severity of arthritis was maintained even after injection of IL-1, which causes all of the wild-type mice to exhibit a severe form of the disease (Fig. 2; Table 2). However, serum anti-collagen antibody levels were similar in wild-type (1050 ± 220 μg/ml) and FLAP deficient mice (1200 ± 23 μg/ml). Leukotriene levels in zymosan-injected wild-type mice were similar to nonimmunized animals (compare Table 1 with Table 2). Heterozygous animals had a slight reduction in LTE4 levels, mean of 74% of control, and no detectable leukotriene was produced in homozygous mice.


Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice.

Griffiths RJ, Smith MA, Roach ML, Stock JL, Stam EJ, Milici AJ, Scampoli DN, Eskra JD, Byrum RS, Koller BH, McNeish JD - J. Exp. Med. (1997)

Collagen-induced arthritis in FLAP deficient mice. DBA/1  mice were immunized with chick type II collagen on day 0 and 21. IL-1  was administered subcutaneously on days 45 and 46 to trigger an arthritic  flare. Disease severity was scored by observation of the paws for redness  and swelling. Open circles, +/+ mice; closed triangles, +/− mice; open  squares, −/− mice. Results are mean ± SEM, n = 3 experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196231&req=5

Figure 2: Collagen-induced arthritis in FLAP deficient mice. DBA/1 mice were immunized with chick type II collagen on day 0 and 21. IL-1 was administered subcutaneously on days 45 and 46 to trigger an arthritic flare. Disease severity was scored by observation of the paws for redness and swelling. Open circles, +/+ mice; closed triangles, +/− mice; open squares, −/− mice. Results are mean ± SEM, n = 3 experiments.
Mentions: The severity of collagen-induced arthritis in the FLAPdeficient mice was reduced at all time points compared with wild-type animals (Fig. 2). The total disease score from days 21–56 (Fig. 2, area under the curve) was reduced by a mean of 73%, P <0.001 (Table 2). Heterozygous animals had a smaller, but significant decrease also, mean of 37%, P <0.05. The reduced severity of arthritis was maintained even after injection of IL-1, which causes all of the wild-type mice to exhibit a severe form of the disease (Fig. 2; Table 2). However, serum anti-collagen antibody levels were similar in wild-type (1050 ± 220 μg/ml) and FLAP deficient mice (1200 ± 23 μg/ml). Leukotriene levels in zymosan-injected wild-type mice were similar to nonimmunized animals (compare Table 1 with Table 2). Heterozygous animals had a slight reduction in LTE4 levels, mean of 74% of control, and no detectable leukotriene was produced in homozygous mice.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department 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.

Show MeSH
Related in: MedlinePlus