Increased Th1 immune response in SERPINB3 transgenic mice during acute liver failure.
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.
Clinica Medica 5,  Department of Medicine, University of Padova, Via Giustiniani, 2 - 35128 Padova.
Gianmarco
G
Villano
Francesca
F
Lunardi
Cristian
C
Turato
Sami
S
Schiff
Natascia
N
Tono
Francesca
F
Campagna
Angelo
A
Gatta
Piero
P
Amodio
Fiorella
F
Calabrese
Patrizia
P
Pontisso
D000082:Acetaminophen / Q000009:adverse effects / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001921:Brain / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology* / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000473:pathology; D015843:Serpins / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
D018712:Analgesics, Non-Narcotic; D016207:Cytokines; C495969:Serpinb3b protein, mouse; D015843:Serpins; D000082:Acetaminophen