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. 2012 Aug 15;94(3):211-7.
doi: 10.1097/TP.0b013e318259d38e.

VSports - Endoplasmic reticulum stress modulates liver inflammatory immune response in the pathogenesis of liver ischemia and reperfusion injury

Jun Liu  1 , Feng Ren, Qiao Cheng, Li Bai, Xiuda Shen, Feng Gao, Ronald W Busuttil, Jerzy W Kupiec-Weglinski, Yuan Zhai
Affiliations

Endoplasmic reticulum stress modulates liver inflammatory immune response in the pathogenesis of liver ischemia and reperfusion injury

Jun Liu et al. Transplantation. .

Abstract

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. VSports手机版.

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. V体育安卓版.

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 V体育ios版. 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 VSports最新版本. .

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Figures

Figure 1
Figure 1
ER stress enhances TLR4-induced macrophage pro-inflammatory immune response. RAW cells were first incubated with Tunicamycin (TM) or Antimycin (AM), followed by LPS stimulation, as described in Material and Methods. Cells were harvested after 15 min, 30 min, 1 h or 2 h after LPS stimulation, and cell lysates were analyzed for NF-kB, JNK, Erk and p38 phosphorylation, as well as β-actin protein levels by Western blots (a). In a separate experiment, RAW cells were harvested after 4 h-long LPS stimulation and total RNA was isolated and subjected to qRT-PCR analysis (b). Bone-marrow-derived macrophages were stimulated first with ER stress agent Tm or Tg, followed by 24h LPS stimulation. Culture supernatants were harvested and TNF-a levels were measured by ELISA (c). Mouse hepatoma cell line Hepa-1, was stimulated with either control (-) or LPS-stimulated (S) RAW cell culture supernatant w/ or w/o pre-incubation with Thapsigargin (Tg). Cells were harvested after 4 h of stimulation and total RNA was isolated and subjected to qRT-PCR analysis (d). Representative results of 3 separate experiments.
Figure 2
Figure 2
ER stress increases hepatocyte sensitivity to TNF-α induced cell death. Hepa-1 (a) or primary hepatocytes from B6 mice (b) cells were pre-incubated with vehicle control or Tg, followed by TNF-α stimulation. Cell death was measured at 24 or 48 h by LDH assay. In a separate experiment, Tg-treated hepa-1 cells were harvested after 15 min, 30 min, 1 h and 2 h of TNF-α stimulation. Cell lysates were subjected to Western blot analysis of p-NF-κB, IκB and β-actin (c). Representative results of 3 separate experiments.
Figure 3
Figure 3
Liver IR triggers ER stress response. Ischemic liver lobes were harvested at different time points of reperfusion (after 90 min of warm ischemia), as described in Material and Methods. Tissue lysates were subjected to Western blot analysis for XBP1, ATF6, ATF4, and β-actin. Representative results of 2 separate experiments.
Figure 4
Figure 4
PBA protects livers from IRI by depressing local pro-inflammatory immune response. PBA was administered 12 h prior to the ischemia insult (10 mg/kg, i.p). Liver injury and immune response were evaluated at 2 h and 6 h of reperfusion by (a) measuring sALT levels, Suzuki's scores of liver tissue damage and liver histology (H&E staining); n=8/group. (b) qRT-PCR of liver inflammatory gene expression programs (IL-12p40, IL-10, TNF-α, CXCL10); n=3/group.
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