Description:
Abstract Danger signals provided by pathogens are sensed by specialized receptors, Toll-like receptors (TLR), on the cell surface of antigen presenting cells (APC) leading to activation of dendritic cells (DC) accompanied by their phenotypic and functional changes. Activation of DC via the TLR is believed to be a critical event regulating the strength and outcome of an immunological response. IL-10 is an immunosuppressive cytokine shown to have inhibitory effects on function and differentiation of APC by interfering with signaling pathways involved in DC activation like the PI3-kinase or NFκB pathway. In our study we analyzed the function of human dendritic cells generated in the presence of IL-10 upon activation by Toll-like receptor ligands (TLR2, TLR3, TLR4, TLR7/8). Exposure of DCs to IL-10 resulted in a skewed phenotypic maturation in response to stimuli provided by TLR ligands, a reduced production of cytokines like IL-12, IL-6 or TNF-α and an impaired capacity to stimulate T cell activation. Furthermore, CCR7 upregulation in DC exposed to TLR stimulation as well as migration toward CCL19/MIP-3β were strongly reduced. As a suitable mechanism for these effects, IL-10 was found to downregulate MyD88, an essential adaptor molecule for TLR signaling, and to decrease TLR-induced nuclear expression of the NFκB transcription factor members c-Rel and Rel-B as well as IRF-3 and IRF-8. This was not due to the inhibition of the MAP kinase pathway as phosphorylation of p38 and ERK was not affected but was rather mediated by inhibitory effects on the PI3-kinase pathway. IL-10 treatment of APC resulted in a reduced TLR induced mTOR phosphorylation. In summary, our results demonstrate that IL-10 can inhibit TLR-mediated activation of APC via a MyD88-dependent and independent pathway.