PMID- 23734212
OWN - NLM
STAT- MEDLINE
DCOM- 20140106
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 5
DP  - 2013
TI  - Clostridium perfringens beta-toxin induces necrostatin-inhibitable, 
      calpain-dependent necrosis in primary porcine endothelial cells.
PG  - e64644
LID - 10.1371/journal.pone.0064644 [doi]
LID - e64644
AB  - Clostridium perfringens beta-toxin (CPB) is a beta-barrel pore-forming toxin and an 
      essential virulence factor of C. perfringens type C strains, which cause fatal 
      hemorrhagic enteritis in animals and humans. We have previously shown that CPB is 
      bound to endothelial cells within the intestine of affected pigs and humans, and 
      that CPB is highly toxic to primary porcine endothelial cells (pEC) in vitro. The 
      objective of the present study was to investigate the type of cell death induced 
      by CPB in these cells, and to study potential host cell mechanisms involved in 
      this process. CPB rapidly induced lactate dehydrogenase (LDH) release, propidium 
      iodide uptake, ATP depletion, potassium efflux, a marked rise in intracellular 
      calcium [Ca(2+)]i, release of high-mobility group protein B1 (HMGB1), and caused 
      ultrastructural changes characteristic of necrotic cell death. Despite a certain 
      level of caspase-3 activation, no appreciable DNA fragmentation was detected. 
      CPB-induced LDH release and propidium iodide uptake were inhibited by 
      necrostatin-1 and the two dissimilar calpain inhibitors PD150606 and calpeptin. 
      Likewise, inhibition of potassium efflux, chelation of intracellular calcium and 
      treatment of pEC with cyclosporin A also significantly inhibited CPB-induced LDH 
      release. Our results demonstrate that rCPB primarily induces necrotic cell death 
      in pEC, and that necrotic cell death is not merely a passive event caused by 
      toxin-induced membrane disruption, but is propagated by host cell-dependent 
      biochemical pathways activated by the rise in intracellular calcium and 
      inhibitable by necrostatin-1, consistent with the emerging concept of programmed 
      necrosis ("necroptosis").
FAU - Autheman, Delphine
AU  - Autheman D
AD  - Institute of Infectious Diseases, Medical Faculty, University of Bern, Bern, 
      Switzerland.
FAU - Wyder, Marianne
AU  - Wyder M
FAU - Popoff, Michel
AU  - Popoff M
FAU - D'Herde, Katharina
AU  - D'Herde K
FAU - Christen, Stephan
AU  - Christen S
FAU - Posthaus, Horst
AU  - Posthaus H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130529
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Acrylates)
RN  - 0 (Bacterial Toxins)
RN  - 0 (CPB protein, Clostridium perfringens)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Dipeptides)
RN  - 0 (HMGB1 Protein)
RN  - 0 (Imidazoles)
RN  - 0 (Indoles)
RN  - 0 (PD 150606)
RN  - 0 (necrostatin-1)
RN  - 18X9FR245W (calpeptin)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 3.4.22.- (Calpain)
RN  - RWP5GA015D (Potassium)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Acrylates/pharmacology
MH  - Animals
MH  - Bacterial Toxins/*pharmacology
MH  - Blotting, Western
MH  - Calcium/metabolism
MH  - Calpain/antagonists & inhibitors/*metabolism
MH  - Cell Membrane/drug effects/metabolism/ultrastructure
MH  - Cells, Cultured
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - DNA Fragmentation/drug effects
MH  - Dipeptides/pharmacology
MH  - Endothelial Cells/*drug effects/metabolism/pathology
MH  - Flow Cytometry
MH  - HMGB1 Protein/metabolism
MH  - Imidazoles/*pharmacology
MH  - Indoles/*pharmacology
MH  - Intracellular Space/drug effects/metabolism
MH  - Ion Transport/drug effects
MH  - L-Lactate Dehydrogenase
MH  - Microscopy, Electron, Transmission
MH  - Necrosis
MH  - Potassium/metabolism
MH  - Swine
PMC - PMC3667183
COIS- Competing Interests: MP is an academic Editor for PLOS ONE. This does not alter 
      the authors' adherence to all the PLOS ONE policies on sharing data and 
      materials.
EDAT- 2013/06/05 06:00
MHDA- 2014/01/07 06:00
PMCR- 2013/05/29
CRDT- 2013/06/05 06:00
PHST- 2013/01/29 00:00 [received]
PHST- 2013/04/17 00:00 [accepted]
PHST- 2013/06/05 06:00 [entrez]
PHST- 2013/06/05 06:00 [pubmed]
PHST- 2014/01/07 06:00 [medline]
PHST- 2013/05/29 00:00 [pmc-release]
AID - PONE-D-13-04388 [pii]
AID - 10.1371/journal.pone.0064644 [doi]
PST - epublish
SO  - PLoS One. 2013 May 29;8(5):e64644. doi: 10.1371/journal.pone.0064644. Print 2013.