The Journal of Experimental Medicine
Torrey Pines Biolabs
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published 2 August 2004. doi:10.1084/jem.20040435
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 3, 367-376
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 1550K)
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 Xanthoulea, S.
Right arrow Articles by Kollias, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xanthoulea, S.
Right arrow Articles by Kollias, G.
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?
Tumor Necrosis Factor (TNF) Receptor Shedding Controls Thresholds of Innate Immune Activation That Balance Opposing TNF Functions in Infectious and Inflammatory Diseases

Sofia Xanthoulea1, Manolis Pasparakis2, Stavroula Kousteni3, Cord Brakebusch4, David Wallach4, Jan Bauer5, Hans Lassmann5, and George Kollias1

1 Institute of Immunology, Biomedical Sciences Research Center "Al. Fleming," Vari 166-72, Greece
2 European Molecular Biology Laboratory, Mouse Biology Programme, Monterotondo 00016, Italy
3 Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR 72205
4 Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
5 Brain Research Institute, University of Vienna, Wien A-1090, Austria

Address correspondence to George Kollias, Institute of Immunology, Biomedical Sciences Research Centre "Al. Fleming," 34 Al. Fleming St., Vari 166-72, Greece. Phone: 21-0-9656507; Fax: 21-0-9656563; email: g.kollias{at}fleming.gr

Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor–dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.

Key Words: TRAPS • arthritis • EAE • chronic hepatitis • LPS toxicity

S. Xanthoulea and M. Pasparakis contributed equally to this work.

C. Brakebusch's present address is Max Planck Institute for Biochemistry, Dept. of Molecular Medicine, Martinsried 82152, Germany.

Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MEF, mouse embryonic fibroblast; MOG, myelin oligodendrocyte glycoprotein; NO, nitric oxide; poly IC, polyinosinic-polycytidylic acid; PTx, pertussis toxin; TRAPS, TNFR1-associated periodic syndromes.


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