Defective generation of a humoral immune response is associated with a reduced incidence and severity of collagen-induced arthritis in microsomal prostaglandin E synthase-1 null mice.
Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase and specifically catalyzes the conversion of PGH(2) to PGE(2). The present study demonstrates the effect of genetic deletion of mPGES-1 on the developing immunologic responses and its impact on the clinical model of bovine collagen-induced arthritis. mPGES-1 null and heterozygous mice exhibited decreased incidence and severity of arthritis compared with wild-type mice in a gene dose-dependent manner. Histopathological examination revealed significant reduction in lining hyperplasia and tissue destruction in mPGES-1 null mice compared with their wild-type littermates. mPGES-1 deficient mice also exhibited attenuation of mechanical nociception in a gene dose-dependent manner. In addition, mPGES-1 null and heterozygous mice showed a marked reduction of serum IgG against type II collagen, including subclasses IgG1, IgG2a, IgG2b, IgG2c, and IgG3, compared with wild-type mice, which correlated with the reduction in observed inflammatory features. These results demonstrate for the first time that deficiency of mPGES-1 inhibits the development of collagen-induced arthritis, at least in part, by blocking the development of a humoral immune response against type II collagen. Pharmacologic inhibition of mPGES-1 may therefore impact both the inflammation and the autoimmunity associated with human diseases such as rheumatoid arthritis.
Division of Rheumatology, Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.
Fumiaki
F
Kojima
Mohit
M
Kapoor
Lihua
L
Yang
Erica L
EL
Fleishaker
Martin R
MR
Ward
Seetha U
SU
Monrad
Ponnappa C
PC
Kottangada
Charles Q
CQ
Pace
James A
JA
Clark
Jerold G
JG
Woodward
Leslie J
LJ
Crofford
D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002417:Cattle; D024043:Collagen Type II / Q000008:administration & dosage / Q000276:immunology*; D051545:Cyclooxygenase 1 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D006580:Genetic Carrier Screening; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood / Q000502:physiology; D007075:Immunoglobulin M / Q000096:biosynthesis; D015994:Incidence; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012720:Severity of Illness Index
D024043:Collagen Type II; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008565:Membrane Proteins; D012333:RNA, Messenger; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse