Distinct response of liver myeloid dendritic cells to endotoxin is mediated by IL-27

Background/Aims: The liver lies downstream of the gut, and is constantly exposed to bacteria. Liver dendritic cells (DC) are known to possess properties of tolerance, and respond to LPS differently when compared to conventional DC, but the underlying mechanisms are not completely understood. The aim of this study was to evaluate liver DC response to LPS stimulation. Methods: Liver or spleen derived DC were isoloated from mice treated with plasmid-GM-CSF hydrodynamic injection. The surface molecules and TLR4 expression on DC and cytokine productions of LPS stimulated DC were determinded by FACS analysis, ELISA and qPCR. The ability of DC to elicit T cell responses and differentiation were examined by MLR/CTL assay and qPCR for molecular markers related to Th1/Th2/Treg. Results: In this study, we demonstrated that the threshold of LPS stimulation for liver DC was markedly higher than spleen DC, even though the expression of TLR4 on both DCs was comparable. In contrast to spleen DC that produced high levels of IL-12 and induced Th1 response upon LPS stimulation, LPS-liver DC preferentially produced IL-10 and IL-27, instead of IL-12. In addition, liver DC induced T cell hyporesponsiveness, associated with selective expansion of CD4(+)Foxp3(+)T regulatory cells. Addition of exogenous IL-12 only slightly enhanced liver DC-induced T cell response. Interestingly, abrogation of IL-27 ligation by using IL-27R(-/-) T cells synergistically augmented the effect of IL-12, suggesting that IL-27 produced by liver DC plays a crucial role in induction of T cell hyporesponsiveness. Conclusions: Liver DC respond distinctly to LPS stimulation by secreting IL-27 which synergizes with silencing of bioactive IL-12 activity leading to profound T cell inhibition. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.