PMID- 15611291
OWN - NLM
STAT- MEDLINE
DCOM- 20050324
LR  - 20220223
IS  - 0022-1007 (Print)
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Linking)
VI  - 200
IP  - 12
DP  - 2004 Dec 20
TI  - Anthrolysin O and other gram-positive cytolysins are toll-like receptor 4 
      agonists.
PG  - 1647-55
AB  - 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.
FAU - Park, Jin Mo
AU  - Park JM
AD  - 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, USA.
FAU - Ng, Vincent H
AU  - Ng VH
FAU - Maeda, Shin
AU  - Maeda S
FAU - Rest, Richard F
AU  - Rest RF
FAU - Karin, Michael
AU  - Karin M
LA  - eng
GR  - R01 AI061712/AI/NIAID NIH HHS/United States
GR  - U54 AI057168/AI/NIAID NIH HHS/United States
GR  - AI61712/AI/NIAID NIH HHS/United States
GR  - U54 AI57168/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (Antigens, Bacterial)
RN  - 0 (Bacterial Proteins)
RN  - 0 (Bacterial Toxins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Pore Forming Cytotoxic Proteins)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Toll-Like Receptors)
RN  - 0 (anthrax toxin)
RN  - 0 (anthrolysin O, Bacillus anthracis)
RN  - 126465-35-8 (Perforin)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Anthrax/metabolism/pathology
MH  - Antigens, Bacterial/toxicity
MH  - Apoptosis/*drug effects
MH  - Bacillus anthracis/*chemistry
MH  - Bacterial Proteins/chemistry/*isolation & purification/*toxicity
MH  - Bacterial Toxins/toxicity
MH  - Bone Marrow Cells/cytology/*metabolism
MH  - MAP Kinase Signaling System/drug effects
MH  - Macrophage Activation/drug effects
MH  - Macrophages/*metabolism
MH  - Membrane Glycoproteins/*agonists/chemistry/*isolation & 
      purification/metabolism/pharmacology/*toxicity
MH  - Mice
MH  - Perforin
MH  - Pore Forming Cytotoxic Proteins
MH  - Receptors, Cell Surface/*agonists/metabolism
MH  - Toll-Like Receptor 4
MH  - Toll-Like Receptors
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC2211988
EDAT- 2004/12/22 09:00
MHDA- 2005/03/25 09:00
PMCR- 2005/06/20
CRDT- 2004/12/22 09:00
PHST- 2004/12/22 09:00 [pubmed]
PHST- 2005/03/25 09:00 [medline]
PHST- 2004/12/22 09:00 [entrez]
PHST- 2005/06/20 00:00 [pmc-release]
AID - jem.20041215 [pii]
AID - 20041215 [pii]
AID - 10.1084/jem.20041215 [doi]
PST - ppublish
SO  - J Exp Med. 2004 Dec 20;200(12):1647-55. doi: 10.1084/jem.20041215.