The Journal of Experimental Medicine
Avanti Polar Lipids, Inc.
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
A correction to this article has been published: Spiller et al., J. Exp. Med. 205 (9) 2177
Published online July 21, 2008
doi:10.1084/jem.20071990
The Journal of Experimental Medicine, Vol. 205, No. 8, 1747-1754
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Spiller et al.
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 2118K)
Right arrow PPT slides of all figures
Right arrow Supplemental Material Index
Right arrow Correction (v205,p2177)
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 Spiller, S.
Right arrow Articles by Kirschning, C. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Spiller, S.
Right arrow Articles by Kirschning, C. J.
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?

BRIEF DEFINITIVE REPORT

 TLR4-induced IFN-{gamma} production increases TLR2 sensitivity and drives Gram-negative sepsis in mice

Stephan Spiller1, Greg Elson2, Ruth Ferstl1, Stefan Dreher1, Thomas Mueller1, Marina Freudenberg3, Bruno Daubeuf2, Hermann Wagner1, and Carsten J. Kirschning1

1 Institute of Medical Microbiology, Immunology, and Hygiene, Technische Universität München, 81675 Munich, Germany
2 Novimmune S.A., 1228 Plan-Les-Ouates, Switzerland
3 Max Planck Institute of Immunobiology, 79108 Freiburg, Germany

CORRESPONDENCE Carsten J. Kirschning:carsten.kirschning{at}lrz.tum.de

Gram-negative bacterial infection is a major cause of sepsis and septic shock. An important inducer of inflammation underlying both syndromes is the cellular recognition of bacterial products through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). We identified a novel antagonistic mAb (named 1A6) that recognizes the extracellular portion of the TLR4–MD-2 complex. If applied to mice before infection with clinical isolates of Salmonella enterica or Escherichia coli and subsequent antibiotic therapy, 1A6 prevented otherwise fatal shock, whereas application of 1A6 after infection was ineffective. In contrast, coapplication of 1A6 and an anti-TLR2 mAb up to 4 h after infection with Gram-negative bacteria, in combination with the start of antibiotic therapy (mimicking clinical conditions), provided robust protection. Consistent with our findings in mice, dual blockade of TLR2 and TLR4 inhibited TNF-{alpha} release from human peripheral blood mononuclear cells upon Gram-negative bacterial infection/antibiotic therapy. Both murine splenocytes and human PBMCs released IFN-{gamma} in a TLR4-dependent manner, leading to enhanced surface TLR2 expression and sensitivity for TLR2 ligands. Our results implicate TLR2 as an important, TLR4-driven sensor of Gram-negative bacterial infection and provide a rationale for blockade of both TLRs, in addition to antibiotic therapy for the treatment of Gram-negative bacterial infection.

S. Spiller and G. Elson contributed equally to this paper.

© 2008 Spiller et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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