Increased Th1 immune response in SERPINB3 transgenic mice during acute liver failure

Abstract

Acute liver failure (ALF) is characterized by severe neurological complications, known as acute hepatic encephalopathy, where brain ammonia and inflammatory processes play a dominant role. In experimental models of acute liver failure SERPINB3 was found significantly increased in microglia, the intrinsic immune cells of the central nervous system. The aim of the present study was to investigate the extent of brain tissue damage and the inflammatory milieu in experimental acute liver failure using a SERPINB3-transgenic mouse model. C57BL/6J wild-type and transgenic mice were inoculated with acetaminophen or phosphate-buffered saline and sacrificed 20 h postinjection. Proliferation and apoptotic activity were analyzed in brain tissue by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique. The expression of cytokines was analysed in brain and liver tissue by real time polymerase chain reaction and in the corresponding serum samples using a Bio-Plex system. Acetaminophen induced a significantly lower body temperature and shorter survival in transgenic than in wild-type mice, despite liver function was similar in both groups. The brain of transgenic mice, expressing SERPINB3 positivity in microglia, showed increased glial cell number, associated to significant lower apoptotic death events, compared with wild-type mice. In mice injected with acetaminophen, remarkably higher values of cytokines mRNA were observed in the liver of both groups, with a trend toward higher values in transgenic animals. In brain tissue similar increase of tumor necrosis factor-α was detected in transgenic and wild-type mice, while IL-10 mRNA increased only in the wild-type group. A remarkable increase of circulating Th1 cytokines was detected in serum of transgenic mice, while in the wild-type group they remained rather unchanged. These figures were associated with lower levels of granulocyte macropage colony-stimulating factor, despite similar increase of IL-10 values in both groups. In conclusion, in acute liver failure SERPINB3 determines an enhanced inflammatory background, mainly mediated by higher levels of Th1 proinflammatory cytokines.

The protease‐inhibitor SerpinB3 as a critical modulator of the stem‐like subset in human cholangiocarcinoma

“…[23][24][25][26] High SB3 levels have been recently detected in HCC tissue of patients with early tumour recurrence after surgical resection, suggesting their involvement in liver malignancy. [23][24][25][26] SB3 is expressed in human liver progenitor cells, 27 as indicated by its detection in EpCAM + cell fractions sorted from human foetal and adult livers and in ductular liver structures expressing stem/ progenitor cell markers. Furthermore, the mouse homologous, SerpinB3b, was induced by the administration of lipopolysaccharide and D-galactosamine, a model of liver stem/progenitor cell activation.…”

HCV genotype 3 and squamous cell carcinoma antigen (SCCA)‐IgM are independently associated with histological features of NASH in HCV‐infected patients

“…It is also capable to induce epithelial–mesenchymal transition, with increased invasiveness potential , and to induce TGF‐beta . A recent study in a mouse model of acute liver failure has demonstrated that the presence of SERPINB3 determines an enhanced inflammatory background, mainly mediated by higher levels of Th1 proinflammatory cytokines . At the serological level, high or increasing levels of SCCA‐IgM immune complexes were associated with more advanced liver disease and increased risk of HCC development .…”

The molecular signature of impaired diabetic wound healing identifies serpinB3 as a healing biomarker

“…5 Summary of the study design. The figure depicts the benchmark for the identification and validation of candidate pathogenic factors and how they can be distinguished from bystander biomarkers in the present study Despite A1at-SerpinB3 TG mice having several pathological and non-pathological features comparable with those of WT mice [21][22][23], including an increased lifespan [24], we did not find any difference in the wound healing process. This indicates that, at least in this experimental model, a high serpinB3 level is in itself insufficient to improve wound healing and seems to argue against a direct role for serpinB3 in the healing process.…”

“…[20]. It has been previously shown to be involved in wound healing processes, including epithelial-to-mesenchymal transition [21], inflammation [22] and apoptosis [23]. Proteomic data, as well as gene and protein analysis, showed higher levels of serpinB3 in RH compared with NH wounds.…”