The Journal of Experimental Medicine
Torrey Pines Biolabs
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published 20 December 2004. doi:10.1084/jem.20041215
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 12, 1647-1655
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 1791K)
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 Park, J. M.
Right arrow Articles by Karin, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Park, J. M.
Right arrow Articles by Karin, M.
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?
Anthrolysin O and Other Gram-positive Cytolysins Are Toll-like Receptor 4 Agonists

Jin Mo Park1, Vincent H. Ng2, Shin Maeda1, Richard F. Rest2, and Michael Karin1

1 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093
2 Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129

Address correspondence to Michael Karin, Laboratory of Gene Regulation and Signal Transduction, Dept. of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093. Phone: (858) 534-1361; Fax: (858) 534-8158; email: karinoffice{at}ucsd.edu

Exposure of bone marrow–derived macrophages (BMDMs) to low concentrations of Bacillus anthracis lethal toxin (LT), whose catalytic subunit is lethal factor (LF), results in induction of a robust apoptotic response dependent on activation of Toll-like receptor (TLR)4. A similar TLR4-dependent apoptotic response is observed when BMDMs are infected with live B. anthracis (Sterne strain). However, TLR4 is considered to be a specific signaling receptor for lipopolysaccharide (LPS), a typical product of gram-negative bacteria, whereas B. anthracis is gram-positive. To understand how B. anthracis can activate TLR4, we analyzed its culture supernatants and found them to contain a potent TLR4-stimulating activity that can also induce apoptosis in macrophages in which the antiapoptotic p38 MAP kinase (whose activation is prevented by LF) was inhibited. Purification of this activity suggested it consists of anthrolysin O (ALO), a member of the cholesterol-dependent cytolysin (CDC) family. We show that recombinant ALO can activate TLR4 in a manner independent of LPS contamination and, together with LT, can induce macrophage apoptosis. We also provide genetic evidence that ALO is required for induction of macrophage apoptosis in response to infection with live B. anthracis and that other CDC family members share the ability to activate TLR4.

Key Words: macrophage • anthrax • innate immunity • apoptosis • infection

Abbreviations used in this paper: ALO, anthrolysin O; BHI, brain heart infusion; BMDM, BM-derived macrophage; CDC, cholesterol-dependent cytolysin; CM, conditioned media; EF, edema factor; LF, lethal factor; LT, lethal toxin; MAPK, mitogen-activated protein kinase; MKK, MAPK kinase; PA, protective antigen; PFO, perfringolysin O; SLO, streptolysin O; TLR, Toll-like receptor.


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