Oxidized Phospholipids Negatively Regulate Dendritic Cell Maturation Induced by TLRs and CD40

Abstract

Maturation of dendritic cells (DCs) induced by pathogen-derived signals via TLRs is a crucial step in the initiation of an adaptive immune response and therefore has to be well controlled. In this study, we demonstrate that oxidized phospholipids (ox-PLs), which are generated during infections, apoptosis, and tissue damage, interfere with DC activation, preventing their maturation. ox-PLs blocked TLR-3- and TLR-4-mediated induction of the costimulatory molecules CD40, CD80, CD83, and CD86, the cytokines IL-12 and TNF, as well as lymphocyte stimulatory capacity. CD40 and TLR-2-mediated cytokine production was also inhibited, whereas up-regulation of costimulatory molecules via these receptors was not affected by ox-PLs. Thus, formation of ox-PLs during the course of an inflammatory response may represent a negative-feedback loop preventing excessive and sustained immune reactions through regulating DC maturation.

Oxidized Phospholipid Inhibition of Toll-like Receptor (TLR) Signaling Is Restricted to TLR2 and TLR4

“…4) suggests that OxPAPC does not mediate anti-inflammatory effects via modulation of these mediators. Nevertheless, it should be noted that in certain cell types, such as dendritic cells, OxPAPC may exert immunosuppressive effects independently of its effects on direct inhibition of TLR-signaling pathways (25).…”

“…Because stimulation of Toll-like receptor (TLR) signaling has been shown to play a central role in the induction of inflammation, oxidant release, and tissue damage in many different disease models (21)(22)(23), it is notable that OxPAPC potently inhibits the ability of LPS to stimulate TLR4-dependent signaling in macrophages, dendritic cells, and endothelial cells (3,10,11,17,24,25). The mechanisms by which OxPAPC inhibits LPS signaling are currently under debate, and numerous potential models have been put forward.…”

VB-201, an oxidized phospholipid small molecule, inhibits CD14- and Toll-like receptor-2-dependent innate cell activation and constrains atherosclerosis

“…While the majority of studies attributed a proinflammatory role to Ox-PLs, reports have shown that Ox-PLs can protect mice from endotoxin-induced septic shock [28], down-regulate T cell effector function [29] and inhibit TLR-2-and TLR-4-mediated signalling events in dendritic cells (DC) [30,31], alluding to an anti-inflammatory role for Ox-PLs.…”

New cellular tools reveal complex epithelial–mesenchymal interactions in hepatocarcinogenesis

“…The expression of the junctional proteins plakoglobin and N-cadherin, as observed in the MF-lines, has been ELISA; number in parentheses gives concentration of cytokine in pg ml À1 medium. e FACS analyses according to (Pfistershammer et al, 2004;Bluml et al, 2005). Immunoflourescence.…”

“…Immunoreactions were visualised by application of cye-dye-conjugated secondary antibodies and TCS-SP confocal microscopy (Leica, Heidelberg, FRG). Detailed discription of FACS analyses of the semi-adherent cell lines and antisera applied are given elsewhere (Pfistershammer et al, 2004;Bluml et al, 2005). ELISA-kits were applied according to the manufacturers' instructions.…”