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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17 March 1997
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March 17 1997
Collagen-induced Arthritis Is Reduced in 5-Lipoxygenase-activating Protein-deficient Mice
Richard J. Griffiths,
Richard J. Griffiths
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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MaryAlice Smith,
MaryAlice Smith
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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Marsha L. Roach,
Marsha L. Roach
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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Jeffrey L. Stock,
Jeffrey L. Stock
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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Ethan J. Stam,
Ethan J. Stam
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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A.J. Milici,
A.J. Milici
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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Deborah N. Scampoli,
Deborah N. Scampoli
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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James D. Eskra,
James D. Eskra
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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Robert S. Byrum,
Robert S. Byrum
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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Beverly H. Koller,
Beverly H. Koller
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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John D. McNeish
John D. McNeish
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
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Richard J. Griffiths
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
MaryAlice Smith
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
Marsha L. Roach
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
Jeffrey L. Stock
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
Ethan J. Stam
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
A.J. Milici
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
Deborah N. Scampoli
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
James D. Eskra
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
Robert S. Byrum
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
Beverly H. Koller
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
John D. McNeish
From the *Department of *Cancer, Immunology, and Infectious Diseases, ‡Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and §Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248
Address correspondence to Dr. John D. McNeish, Molecular Sciences, Central Research Division, Pfizer, Inc., Eastern Point Road, Groton, CT 06340
1 Abbreviations used in this paper: 5-LO, 5-lipoxygenase; ES, embryonic stem; FLAP, 5-lipoxygenase-activating protein; HETE, hydroxyeicosatetraenoic acid; LTB4, leukotriene B4.
Received:
December 16 1996
Revision Received:
January 20 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 185 (6): 1123–1130.
Article history
Received:
December 16 1996
Revision Received:
January 20 1997
Citation
Richard J. Griffiths, MaryAlice Smith, Marsha L. Roach, Jeffrey L. Stock, Ethan J. Stam, A.J. Milici, Deborah N. Scampoli, James D. Eskra, Robert S. Byrum, Beverly H. Koller, John D. McNeish; Collagen-induced Arthritis Is Reduced in 5-Lipoxygenase-activating Protein-deficient Mice. J Exp Med 17 March 1997; 185 (6): 1123–1130. doi: https://doi.org/10.1084/jem.185.6.1123
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