Distinct response of liver myeloid dendritic cells to endotoxin is mediated by IL-27.
OBJECTIVE
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.
Chen
Yun
Y
Department of Immunology, Learner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Jiang
Guoping
G
Yang
Horng-Ren
HR
Gu
Xiaodong
X
Wang
Lianfu
L
Hsieh
Ching-Chuan
CC
Chou
Hong-Shiue
HS
Fung
John J
JJ
Qian
Shiguang
S
Lu
Lina
L
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D004731:Endotoxins; C486767:Il27 protein, mouse; D007378:Interleukins; D008070:Lipopolysaccharides; D018123:Receptors, Interleukin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor