PPAR-gamma Agonists Inhibit Toll-Like Receptor Mediated Activation of Dendritic Cells Via the MAP Kinase and NF-kB Pathways.

Dendritic cells (DC) play an important role in initiating and maintaining of primary immune responses. However, little is known about the termination of once induced immunological responses. Cyclopentenone prostaglandins (15d-PGJ2, PGD2) are produced during the late phase of inflammation due to upregulation of COX2 and can lead to the resolution of an inflammation by activation of PPAR-gamma dependent and independent pathways. In this study we analyzed the effects of 15d-PGJ2 and the synthetic PPAR-gamma ligand troglitazone (TGZ) on the immunogenicity of monocyte derived DC upon stimulation with toll-like receptor (TLR) ligands. Activation of PPAR-gamma resulted in a reduced activation of DC via the TLR ligands 2, 3, 4 and 7 characterized by downregulation of CD83, adhesion and costimulatory molecules. Moreover, these cells secreted lower levels of cytokines and chemokines involved in T lymphocyte activation and recruitment including IL-12 and RANTES. In contrast to these results, MCP-1 production was increased due to the treatment with PPAR-gamma agonists. To determine the mechanisms by which PPAR-gamma regulates DC function we performed Western blot analyses and found that the inhibitory effects on TLR induced DC activation were mediated via inhibition of the NF-kB and MAP kinase pathways. Incubation of DC during the differentiation from monocytes with 15d-PGJ2 or TGZ resulted in downregulation of TLR ligands induced phosphorylation of ERK1 as well as reduced expression of nuclear localized members of the NF-kB family. No effect on the expression of MyD88, an adaptor molecule involved in the signal transduction of TLR, was observed. Our results demonstrate that inhibition of the MAP kinase and NF-kB pathways is critically involved in the regulation of TLR and PPAR-gamma mediated signaling in DC an represent a novel negative feed-back mechanism involved in the resolution of immunological responses.