Abstract
BackgroundTumor Necrosis Factor alpha (TNFα) 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 TNFα utilizes PLD1 to mediate the activation of NFκB and ERK1/2 in human monocytes. The aim of this study was to investigate the role(s) played by phospholipase D1 (PLD1) in TNFα-mediated inflammatory responses in vivo.Methodology/FindingsStudies were performed in vivo using a mouse model of TNFα-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. TNFα triggers a rapid pyrogenic response, but the in vivo silencing of PLD1 protects mice from the TNFα-induced rise in temperature. Similarly TNFα caused an increase in the serum levels of IL-6, MIP-1α and MIP-1β: this increase in cytokine/chemokine levels was inhibited in mice where PLD1 had been silenced. We then induced acute peritonitis with TNFα. Intraperitoneal injection of TNFα 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 TNFα-triggered increase in vascular permeability and phagocyte influx was substantially reduced. Furthermore, we also show that the TNFα-mediated upregulation of the cell adhesion molecules VCAM and ICAM1, in the vascular endothelium, were dependent on PLD1.ConclusionsThese novel data demonstrate a critical role for PLD1 in TNFα-induced inflammation in vivo and warrant further investigation. Indeed, our results suggest PLD1 as a novel target for treating inflammatory diseases, where TNFα play key roles: these include diseases ranging from sepsis to respiratory and autoimmune diseases; all diseases with considerable unmet medical need.
Highlights
Tumor Necrosis Factor alpha (TNFa) is a pleiotropic cytokine extensively studied for its role in the pathogenesis of a variety of disease conditions, which is known to have a wide range of beneficial and deleterious effects in humans [1,2]
These novel data demonstrate a critical role for phospholipase D1 (PLD1) in TNFa-induced inflammation in vivo and warrant further investigation
Our results suggest PLD1 as a novel target for treating inflammatory diseases, where TNFa play key roles: these include diseases ranging from sepsis to respiratory and autoimmune diseases; all diseases with considerable unmet medical need
Summary
Tumor Necrosis Factor alpha (TNFa) is a pleiotropic cytokine extensively studied for its role in the pathogenesis of a variety of disease conditions, which is known to have a wide range of beneficial and deleterious effects in humans [1,2]. TNFa is produced by a variety of cells which include: macrophages, monocytes, lymphocytes, NK cells, eosinophils, keratinocytes, langerhan cells, kupffer cells, glial cells, adipocytes and fibroblasts [1,2,3] This cytokine is known to be produced in response to a wide range of stimuli such as, bacterial toxins (e.g. LPS); infections (bacterial, viral, fungal, mycobacterial and parasitic); antigen-antibody complexes; injury; host inflammatory agents (products of the complement activation, auto-antibodies and cytokines); as well as toxic and non-toxic environmental challenges [1,3]. The aim of this study was to investigate the role(s) played by phospholipase D1 (PLD1) in TNFa-mediated inflammatory responses in vivo
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