The Journal of Experimental Medicine
Avanti Polar Lipids, Inc.
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published online 9 December 2002 doi:10.1084/jem.20020281
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 486K)
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 Kontoyiannis, D.
Right arrow Articles by Kollias, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kontoyiannis, D.
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 Reddit   Add to Technorati  
What's this?
© Rockefeller University Press, 0022-1007/2002/12/1563/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 12, December 16, 2002 1563-1574

Genetic Dissection of the Cellular Pathways and Signaling Mechanisms in Modeled Tumor Necrosis Factor–induced Crohn's-like Inflammatory Bowel Disease

Dimitris Kontoyiannis1, George Boulougouris1, Menelaos Manoloukos1, Maria Armaka1, Maria Apostolaki1, Theresa Pizarro2, Alexey Kotlyarov3, Irmgard Forster4, Richard Flavell5, Matthias Gaestel3, Philip Tsichlis6, Fabio Cominelli2 and George Kollias1

1 Institute for Immunology, Biomedical Sciences Research Center "Al. Fleming," Vari 166-72, Greece
2 Division of Gastroenterology and Hepatology, University of Virginia Health Sciences Center, Charlottesville, VA 22906
3 Institut of Biochemistry, Medical School Hannover, 30625 Hannover, Germany
4 Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, 80333 Munich, Germany
5 Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
6 Molecular Oncology Research Institute, Tufts, New England Medical Center, Boston, MA 02111

Address correspondence to George Kollias, Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming," 14-16 Al. Fleming Street, 166-72 Vari, Greece. Phone: +301 9656507; Fax: +301 9656563; E-mail: g.kollias{at}fleming.gr

Recent clinical evidence demonstrated the importance of tumor necrosis factor (TNF) in the development of Crohn's disease. A mouse model for this pathology has previously been established by engineering defects in the translational control of TNF mRNA (Tnf{Delta}ARE mouse). Here, we show that development of intestinal pathology in this model depends on Th1-like cytokines such as interleukin 12 and interferon {gamma} and requires the function of CD8+ T lymphocytes. Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell–derived TNF can exhibit full pathogenic capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF receptor–deficient mice revealed that TNF signals are equally pathogenic when directed independently to either bone marrow–derived or tissue stroma cell targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase–deficient genetic background. Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.

Key Words: MAPK/SAPK • targeted mutants • CD8+ lymphocytes • apoptosis • intestine


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 Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



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