Cytosolic phospholipase A2alpha-deficient mice are resistant to collagen-induced arthritis.
Pathogenic mechanisms relevant to rheumatoid arthritis occur in the mouse model of collagen-induced arthritis (CIA). Cytosolic phospholipase A2alpha (cPLA2alpha) releases arachidonic acid from cell membranes to initiate the production of prostaglandins and leukotrienes. These inflammatory mediators have been implicated in the development of CIA. To test the hypothesis that cPLA2alpha plays a key role in the development of CIA, we backcrossed cPLA2alpha-deficient mice on the DBA/1LacJ background that is susceptible to CIA. The disease severity scores and the incidence of disease were markedly reduced in cPLA2alpha-deficient mice compared with wild-type littermates. At completion of the study, >90% of the wild-type mice had developed disease whereas none of the cPLA2alpha-deficient mice had more than one digit inflamed. Furthermore, visual disease scores correlated with severity of disease determined histologically. Pannus formation, articular fibrillation, and ankylosis were all dramatically reduced in the cPLA2alpha-deficient mice. Although the disease scores differed significantly between cPLA2alpha mutant and wild-type mice, anti-collagen antibody levels were similar in the wild-type mice and mutant littermates. These data demonstrate the critical role of cPLA2alpha in the pathogenesis of CIA.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Martin
M
Hegen
Linhong
L
Sun
Naonori
N
Uozumi
Kazuhiko
K
Kume
Mary E
ME
Goad
Cheryl L
CL
Nickerson-Nutter
Takao
T
Shimizu
James D
JD
Clark
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001168:Arthritis / Q000209:etiology* / Q000517:prevention & control; D002352:Carrier Proteins / Q000502:physiology; D003094:Collagen / Q000276:immunology*; D051546:Cyclooxygenase 2; D003600:Cytosol / Q000201:enzymology*; D054513:Group IV Phospholipases A2; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood / Q000145:classification; D007527:Isoenzymes / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010741:Phospholipases A / Q000172:deficiency / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype
D058927:5-Lipoxygenase-Activating Proteins; C548593:Alox5ap protein, mouse; D002352:Carrier Proteins; D007074:Immunoglobulin G; D007527:Isoenzymes; D008565:Membrane Proteins; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D003094:Collagen; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2