The Journal of Experimental Medicine
Torrey Pines Biolabs
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 1588K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gilkeson, G. S.
Right arrow Articles by Weinberg, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gilkeson, G. S.
Right arrow Articles by Weinberg, J. B.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*UniGene
*Compound via MeSH
*Substance via MeSH
Medline Plus Health Information
*Autoimmune Diseases
Hazardous Substances DB
*NITRIC OXIDE
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?
© The Rockefeller University Press, 0022-1007/1997/8/365/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 3, August 4, 1997 365-373

Articles

Clinical and Serologic Manifestations of Autoimmune Disease in MRL-lpr/lpr Mice Lacking Nitric Oxide Synthase Type 2

Gary S. Gilkeson*, John S. Mudgett{ddagger}, Michael F. Seldin§, Phil Ruiz||, Audrey A. Alexander, Mary A. Misukonis, David S. Pisetsky, and J. Brice Weinberg

* From the Ralph H. Johnson Veterans Affairs Medical Center and the Medical University of South Carolina, Charleston, South Carolina 29425; {ddagger} Merck Research Laboratories, Rahway, New Jersey 07065; § University of California Davis, Davis, California 95616; || University of Miami Medical Center, Miami, Florida 33136; and the Veterans Affairs and Duke University Medical Centers, Durham, North Carolina 27705

Nitric oxide (NO) is an important mediator of the inflammatory response. MRL–lpr/lpr mice overexpress inducible nitric oxide synthase (NOS2) and overproduce NO in parallel with the development of an autoimmune syndrome with a variety of inflammatory manifestations. In previous studies, we showed that inhibiting NO production with the nonselective nitric oxide synthase (NOS) inhibitor NG-monomethyl–arginine reduced glomerulonephritis, arthritis, and vasculitis in MRL–lpr/lpr mice. To define further the role of NO and NOS2 in disease in MRL–lpr/lpr mice, mice with targeted disruption of NOS2 were produced by homologous recombination and bred to MRL–lpr/lpr mice to the N4 generation. MRL–lpr/lpr littermates homozygous for disrupted NOS2 (–/–), heterozygous for disrupted NOS2 (+/–), or wildtype (+/+) were derived for this study. Measures of NO production were markedly decreased in the MRL-lpr/lpr (–/–) mice compared with MRL-lpr/lpr (+/+) mice, with intermediate production by the MRL-lpr/lpr (+/–) mice. There was no detectable NOS2 protein by immunoblot analysis of the spleen, liver, kidney, and peritoneal macrophages of the (–/–) animals, whereas that of (+/+) was high and (+/–) intermediate. The (–/–) mice developed glomerular and synovial pathology similar to that of the (+/–) and (+/+) mice. However, (–/–) mice and (+/–) mice had significantly less vasculitis of medium-sized renal vessels than (+/+) mice. IgG rheumatoid factor levels were significantly lower in the (–/–) mice as compared with (+/+) mice, but levels of anti-DNA antibodies were comparable in all groups. Our findings show that NO derived from NOS2 has a variable impact on disease manifestations in MRL-lpr/lpr mice, suggesting heterogeneity in disease mechanisms.

Address correspondence to J. Brice Weinberg, MD, VA and Duke University Medical Centers, 508 Fulton Street, Durham, NC 27705. Phone: 919-286-6833; FAX: 919-286-6891; E-mail: brice{at}acpub.duke.edu

The work was supported in part by the Veterans Affairs Research Service, the James R. Swiger Hematology Research Fund, an Arthritis Foundation Biomedical Research Grant, a grant from the Lupus Foundation of America, and National Institutes of Health award AR-39162.

1 Abbreviations used in this paper: ds, double-stranded; NO, nitric oxide; NOS, nitric oxide synthase; ss, single-stranded.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS