Endoplasmic reticulum stress modulates liver inflammatory immune response in the pathogenesis of liver ischemia and reperfusion injury.
BACKGROUND
Although endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of organ ischemia-reperfusion injury (IRI), the underlying mechanisms have yet to be fully elucidated. In particular, because tissue proinflammatory immune response is the key mediator of local IRI, how ER stress impacts liver immune cell activation cascade remains to be determined.


METHODS
In vitro, ER stress in macrophages and hepatocytes were induced by pharmacological agents. Macrophage Toll-like receptor 4 and hepatocyte tumor necrosis factor α responses were studied. In vivo, the induction of ER stress by ischemia-reperfusion and the impact of ER stress amelioration by a small molecule chaperon 4-phenylbutyric acid on liver immune response were studied in a murine partial liver warm ischemia model.


RESULTS
ER-stressed macrophages generated a significantly enhanced proinflammatory immune response against Toll-like receptor 4 stimulation, whereas ER-stressed hepatocytes became more susceptible to tumor necrosis factor α-induced cell death. Ischemia-reperfusion resulted in up-regulations of spliced X-box binding protein 1 and activating transcription factor 6 levels in affected livers. Mice pretreated with 4-phenylbutyric acid were protected from liver IRI, in parallel with diminished local proinflammatory gene induction program.


CONCLUSIONS
Our study documents a potential immune regulatory role of ER stress in the mechanism of liver IRI and provides a rationale for targeting stress response as a new therapeutic means to ameliorate tissue inflammation in organ transplant recipients.
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
Jun
J
Liu
Feng
F
Ren
Qiao
Q
Cheng
Li
L
Bai
Xiuda
X
Shen
Feng
F
Gao
Ronald W
RW
Busuttil
Jerzy W
JW
Kupiec-Weglinski
Yuan
Y
Zhai
D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology; D007107:Immune System; D007249:Inflammation; D007511:Ischemia / Q000473:pathology; D008099:Liver / Q000473:pathology*; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010654:Phenylbutyrates / Q000494:pharmacology; D015427:Reperfusion Injury; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D010654:Phenylbutyrates; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C075773:4-phenylbutyric acid