PMID- 20463923
OWN - NLM
STAT- MEDLINE
DCOM- 20100907
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 5
DP  - 2010 May 5
TI  - Phospholipase D1 mediates TNFalpha-induced inflammation in a murine model of 
      TNFalpha-induced peritonitis.
PG  - e10506
LID - 10.1371/journal.pone.0010506 [doi]
LID - e10506
AB  - BACKGROUND: Tumor Necrosis Factor alpha (TNFalpha) is a pleiotropic cytokine 
      extensively studied for its role in the pathogenesis of a variety of disease 
      conditions, including in inflammatory diseases. We have recently shown that, in 
      vitro, that TNFalpha utilizes PLD1 to mediate the activation of NFkappaB and 
      ERK1/2 in human monocytes. The aim of this study was to investigate the role(s) 
      played by phospholipase D1 (PLD1) in TNFalpha-mediated inflammatory responses in 
      vivo. METHODOLOGY/FINDINGS: Studies were performed in vivo using a mouse model of 
      TNFalpha-induced peritonitis. The role of PLD1 was investigated by functional 
      genomics, utilizing a specific siRNA to silence the expression of PLD1. 
      Administration of the siRNA against PLD1 significantly reduced PLD1 levels in 
      vivo. TNFalpha triggers a rapid pyrogenic response, but the in vivo silencing of 
      PLD1 protects mice from the TNFalpha-induced rise in temperature. Similarly 
      TNFalpha caused an increase in the serum levels of IL-6, MIP-1alpha and 
      MIP-1beta: this increase in cytokine/chemokine levels was inhibited in mice where 
      PLD1 had been silenced. We then induced acute peritonitis with TNFalpha. 
      Intraperitoneal injection of TNFalpha triggered a rapid increase in vascular 
      permeability, and the influx of neutrophils and monocytes into the peritoneal 
      cavity. By contrast, in mice where PLD1 had been silenced, the TNFalpha-triggered 
      increase in vascular permeability and phagocyte influx was substantially reduced. 
      Furthermore, we also show that the TNFalpha-mediated upregulation of the cell 
      adhesion molecules VCAM and ICAM1, in the vascular endothelium, were dependent on 
      PLD1. CONCLUSIONS: These novel data demonstrate a critical role for PLD1 in 
      TNFalpha-induced inflammation in vivo and warrant further investigation. Indeed, 
      our results suggest PLD1 as a novel target for treating inflammatory diseases, 
      where TNFalpha play key roles: these include diseases ranging from sepsis to 
      respiratory and autoimmune diseases; all diseases with considerable unmet medical 
      need.
FAU - Sethu, Swaminathan
AU  - Sethu S
AD  - Department of Physiology, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
FAU - Pushparaj, Peter N
AU  - Pushparaj PN
FAU - Melendez, Alirio J
AU  - Melendez AJ
LA  - eng
GR  - G0700794/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100505
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Chemokines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.1.4.4 (Phospholipase D)
RN  - EC 3.1.4.4 (phospholipase D1)
SB  - IM
MH  - Animals
MH  - Body Temperature/drug effects
MH  - Capillary Permeability/drug effects
MH  - Cell Adhesion Molecules/metabolism
MH  - Chemokines/biosynthesis
MH  - Disease Models, Animal
MH  - Gene Knockdown Techniques
MH  - Inflammation/complications/*enzymology/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Monocytes/drug effects/pathology
MH  - Neutrophil Infiltration/drug effects
MH  - Peritoneum/drug effects/metabolism/pathology
MH  - Peritonitis/blood/complications/*enzymology/*pathology
MH  - Phospholipase D/*metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Tumor Necrosis Factor-alpha/pharmacology
PMC - PMC2864766
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2010/05/14 06:00
MHDA- 2010/09/08 06:00
PMCR- 2010/05/05
CRDT- 2010/05/14 06:00
PHST- 2010/03/04 00:00 [received]
PHST- 2010/04/12 00:00 [accepted]
PHST- 2010/05/14 06:00 [entrez]
PHST- 2010/05/14 06:00 [pubmed]
PHST- 2010/09/08 06:00 [medline]
PHST- 2010/05/05 00:00 [pmc-release]
AID - 10-PONE-RA-16765R1 [pii]
AID - 10.1371/journal.pone.0010506 [doi]
PST - epublish
SO  - PLoS One. 2010 May 5;5(5):e10506. doi: 10.1371/journal.pone.0010506.