Phospholipase D1 mediates TNFalpha-induced inflammation in a murine model of TNFalpha-induced peritonitis.

Abstract

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.

• Authors: Swaminathan Sethu, Peter N Pushparaj, Alirio J Melendez
• Journal: PloS one (PLoS One) Vol. 5 Issue 5 Pg. e10506 (May 05 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20463923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Chemokines
• RNA, Small Interfering
• Tumor Necrosis Factor-alpha
• Phospholipase D
• phospholipase D1

Topics

• Animals
• Body Temperature (drug effects)
• Capillary Permeability (drug effects)
• Cell Adhesion Molecules (metabolism)
• Chemokines (biosynthesis)
• Disease Models, Animal
• Gene Knockdown Techniques
• Inflammation (complications, enzymology, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Monocytes (drug effects, pathology)
• Neutrophil Infiltration (drug effects)
• Peritoneum (drug effects, metabolism, pathology)
• Peritonitis (blood, complications, enzymology, pathology)
• Phospholipase D (metabolism)
• RNA, Small Interfering (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)