β-catenin regulates innate and adaptive immunity in mouse liver ischemia-reperfusion injury.
Dendritic cells (DCs) are critical mediators of immune responses that integrate signals from the innate immune system to orchestrate adaptive host immunity. This study was designed to investigate the role and molecular mechanisms of STAT3-induced β-catenin in the regulation of DC function and inflammatory responses in vitro and in vivo. STAT3 induction in lipopolysaccharide (LPS)-stimulated mouse bone marrow-derived DCs (BMDCs) triggered β-catenin activation by way of GSK-3β phosphorylation. The activation of β-catenin inhibited phosphatase and tensin homolog delete on chromosome 10 (PTEN) and promoted the phosphoinositide 3-kinase (PI3K)/Akt pathway, which in turn down-regulated DC maturation and function. In contrast, knockdown of β-catenin increased PTEN/TLR4 (Toll-like receptor 4), interferon regulatory factor-3 (IRF3), nuclear factor kappa B (NF-κB) activity, and proinflammatory cytokine programs in response to LPS stimulation. In a mouse model of warm liver ischemia and reperfusion injury (IRI), disruption of β-catenin signaling increased the hepatocellular damage, enhanced hepatic DC maturation/function, and PTEN/TLR4 local inflammation in vivo.


CONCLUSIONS
These findings underscore the role of β-catenin to modulate DC maturation and function at the innate-adaptive interface. Activation of β-catenin triggered PI3K/Akt, which in turn inhibited TLR4-driven inflammatory response in a negative feedback regulatory mechanism. By identifying the molecular pathways by which β-catenin regulates DC function, our findings provide the rationale for novel therapeutic approaches to manage local inflammation and injury in IR-stressed liver.
Dumont-UCLA Transplant Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Bibo
B
Ke
Xiu-Da
XD
Shen
Naoko
N
Kamo
Haofeng
H
Ji
Shi
S
Yue
Feng
F
Gao
Ronald W
RW
Busuttil
Jerzy W
JW
Kupiec-Weglinski
D056704:Adaptive Immunity / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D007113:Immunity, Innate / Q000502:physiology*; D008107:Liver Diseases / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051176:beta Catenin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse