Abstract
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.
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