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.
Kojima
Fumiaki
F
Division of Rheumatology, Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.
Kapoor
Mohit
M
Yang
Lihua
L
Fleishaker
Erica L
EL
Ward
Martin R
MR
Monrad
Seetha U
SU
Kottangada
Ponnappa C
PC
Pace
Charles Q
CQ
Clark
James A
JA
Woodward
Jerold G
JG
Crofford
Leslie J
LJ
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