HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kojima, F. Articles by Crofford, L. J. Search for Related Content PubMed PubMed Citation Articles by Kojima, F. Articles by Crofford, L. J.

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 Mice¹

Fumiaki Kojima^*, Mohit Kapoor^*, Lihua Yang^*, Erica L. Fleishaker^*, Martin R. Ward, Seetha U. Monrad, Ponnappa C. Kottangada^*, Charles Q. Pace^*, James A. Clark^*, Jerold G. Woodward and Leslie J. Crofford^2,*

^* Division of Rheumatology, Department of Internal Medicine and Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40536; and Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109

Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase and specifically catalyzes the conversion of PGH₂ to PGE₂. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health/ National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant R01 AR049010, National Institutes of Health Grant EY14060, and a travel award from the Japanese Society of Clinical Pharmacology and Therapeutics.

² Address correspondence and reprint requests to Dr. Leslie J. Crofford, Department of Internal Medicine, Rheumatology Division, Room J-509, Kentucky Clinic, University of Kentucky, Lexington, KY 40536. E-mail address: ljcrof2{at}email.uky.edu

³ Abbreviations used in this paper: mPGES, microsomal PGE synthase; CIA, collagen-induced arthritis; CII, type II collagen; COX, cyclooxygenase; Het, heterozygous; RA, rheumatoid arthritis.