PPAR-γ agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-κB pathways

Abstract

Dendritic cells (DCs) play an important role in initiating and maintaining primary immune responses. However, mechanisms involved in the resolution of these responses are elusive. We analyzed the effects of 15d-PGJ2 and the synthetic peroxisome proliferator-activated receptor (PPAR)-gamma ligand troglitazone (TGZ) on the immunogenicity of human monocyte-derived DCs upon stimulation with toll-like receptor (TLR) ligands. Activation of PPAR-gamma resulted in a reduced stimulation of DCs via the TLR ligands 2, 3, 4, and 7, characterized by down-regulation of costimulatory and adhesion molecules and reduced secretion of cytokines and chemokines involved in T-lymphocyte activation and recruitment. MCP-1 (monocyte chemotactic protein-1) production was increased due to PPAR-gamma activation. Furthermore, TGZ-treated DCs showed a significantly reduced capacity to stimulate T-cell proliferation, emphasizing the inhibitory effect of PPAR-gamma activation on TLR-induced DC maturation. Western blot analyses revealed that these inhibitory effects on TLR-induced DC activation were mediated via inhibition of the NF-kappaB and mitogen-activated protein (MAP) kinase pathways while not affecting the PI3 kinase/Akt signaling. Our data demonstrate that inhibition of the MAP kinase and NF-kappaB pathways is critically involved in the regulation of TLR and PPAR-gamma-mediated signaling in DCs.

Peroxisome Proliferator-Activated Receptor γ Control of Dendritic Cell Function Contributes to Development of CD4+ T Cell Anergy

“…Additionally, we show that PPAR␥ activation decreased LPSinduced phosphorylation of ERK1, thus interfering with MAPK signaling. This is in line with observations made by Appel et al (35), who showed that the PPAR␥ agonist troglitazone interfered with TLR ligand-induced MAPK signaling in human DCs resulting in reduced DC activation. Thus, it appears that the immunostimulatory capacity of DCs is stringently controlled by regulatory mechanisms that involve signaling via PPAR␥.…”

Peroxisome Proliferator-activated Receptor γ Negatively Regulates IFN-β Production in Toll-like Receptor (TLR) 3- and TLR4-stimulated Macrophages by Preventing Interferon Regulatory Factor 3 Binding to the IFN-β Promoter

“…PPAR-␥ is expressed in both murine CD4 and CD8 cells, and PPAR-␥ ligands directly decrease IFN-␥ expression in T cells (20). In dendritic cells, PPAR-␥ agonists have been shown to inhibit TLR-mediated activation of dendritic cell via the MAP kinase and NF-B pathways (21). However, the effect of PPAR-␥ on IFN-␤ production downstream of TLR signaling has not been clarified.…”

Reactive Oxygen Species Level Defines Two Functionally Distinctive Stages of Inflammatory Dendritic Cell Development from Mouse Bone Marrow

“…Hence, zymosan as a ligand for dectin-1 was used together with LPS to stimulate DCs in this model. In contrast, LPS alone was sufficient to stimulate p38 MAPK phosphorylation on Thr 180 and Tyr 182 (21). Before TLR stimulation, interestingly, day 3 ROS lo DCs showed a higher level of background NF-kB p65 phosphorylation and a lower level of p38 MAPK activation than did day 6 ROS hi DCs, suggesting the constitutive presence of a diverse FIGURE 1.…”