Peroxisome proliferator‐activated receptor‐γ agonists inhibit respiratory syncytial virus‐induced expression of intercellular adhesion molecule‐1 in human lung epithelial cells

Abstract

SummaryRespiratory syncytial virus (RSV) is the major causative agent of severe lower respiratory tract disease and death in infants worldwide. The epithelial cells of the airways are the target cells for RSV infection and the site of the majority of the inflammation associated with the disease. However, despite five decades of intensive RSV research there exist neither an effective active vaccine nor a promising antiviral and anti-inflammatory therapy. Recently, peroxisome proliferator-activated receptor-c (PPAR-c), a member of the nuclear hormone receptor superfamily, has been shown to possess anti-inflammatory properties. Therefore, we hypothesized whether the detrimental increase of intercellular adhesion molecule-1 (ICAM-1) on RSV-infected lung epithelial cells (A549 and primary normal human bronchial epithelial cells (NHBE)) might be modulated by natural and synthetic PPAR-c agonists (15d-PGJ 2 , ciglitazone, troglitazone, Fmoc-Leu). Our data show that all PPAR-c agonists under study significantly downregulated the RSV-induced expression of ICAM-1 on A549-and NHBE cells in a dose-dependent manner resulting in a reduced b 2 integrinmediated adhesion of monocytic effector cells (U937) to RSV-infected A549 cell monolayers. In contrast, the PPAR-a agonist bezafibrate had no impact on the RSV-induced ICAM-1 expression. The reduced ICAM-1 expression was associated with a diminished ICAM-1 mRNA level and binding activity of nuclear factor-jB (p65/p50) in A549 cells. These findings suggest that PPARc agonists have beneficial effects in the suppression of the inflammatory response during RSV infection and therefore might have clinical efficacy in the course of severe RSV-infection.

Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) Suppresses Rho GTPases in Human Brain Microvascular Endothelial Cells and Inhibits Adhesion and Transendothelial Migration of HIV-1 Infected Monocytes

“…Consistent with our data, others previously reported a lack of effect on ICAM-1 and VCAM-1 regulation after activation of PPAR␥ in TNF-␣-stimulated human aortic endothelial cells using the natural ligands belonging to the conjugated linoleic acid class of fatty acids (29). It is possible that the effect on the expression of adhesion molecules by PPAR␥ could occur if treatment with PPAR␥ ligands was extended beyond the few hours performed in this study (38,40). Similarly, the PPAR␥ agonist rosiglitazone did not change barrier function of BMVEC monolayers (measured by TEER) or distribution/level of TJ proteins in brain endothelium.…”

Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice

“…PPARg agonists are postulated to act through cell cycle arrest and TGF-b1 inhibition for myofibroblast differentiation and collagen deposition (76,77). Enhanced PPARg was protective against respiratory syncytial virus infection in lung airway epithelial cell lines, and reduced ICAM-1 expression and NF-kB activation was associated with this effect (78). Overall, these observations strongly indicate that PPARg is an important down-regulator of airway inflammation and injury.…”

Nuclear Receptor Signaling Inhibits HIV-1 Replication in Macrophages through Multipletrans-Repression Mechanisms

“…GR has been shown to directly interact with components of both NF-B and AP-1 and to prevent them from interacting with other promoters in vivo (90,95,117,129,135). PPAR␥ has been shown to interact with NF-B p65 (7,27), suggesting that binding to and preventing p65 from interacting with the LTR is a possible mechanism of PPAR␥-mediated trans-repression. LXR has been shown to bind to STATs and prevent their association with gene promoters (87); however, it has never before been shown to interact with NF-B as a means of repressing gene expression.…”