Differential lymphotoxin-beta and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury.
The liver regenerates after acute injury via hepatocyte cell division; during chronic injury, when hepatocyte replication is impaired or blocked, liver progenitor oval cells mediate liver regeneration. If both regeneration options are blocked in animal models, then liver failure and death ensues. The mechanisms underlying oval cell induction, proliferation, and subsequent liver regeneration remain poorly characterized. In particular, cell-signaling pathways that distinguish the alternative pathways are unknown. This study shows that in a mouse model, hepatic expression of lymphotoxin-beta (LTbeta) and interferon gamma (IFNgamma) transcripts is increased in response to the choline-deficient, ethionine-supplemented (CDE) diet, which induces oval cell-mediated liver regeneration. Oval cells express LTbeta and IFNgamma transcripts, contributing to the increased expression in the liver of mice fed the CDE diet. An attenuated oval cell response to such a diet was observed in LTbeta receptor-, LTbeta-, and IFNgamma-gene targeted mice. Loss of LTbeta and LTbeta receptor signaling reduced the number of oval cells expressing A6 and muscle pyruvate kinase. The lack of IFNgamma signaling reduced muscle pyruvate kinase(+), but not A6(+), oval cells. In contrast, partial hepatectomy suppressed LTbeta and IFNgamma transcripts. We also show that IFNgamma induces STAT-3 phosphorylation in an oval cell line. In conclusion, LTbeta, LTbeta receptor, and IFNgamma are involved in oval cell-mediated, but not hepatocyte-mediated, liver regeneration, and the absence of these pathways impairs the oval cell-dependent regenerative response.
Akhurst
Barbara
B
School of Biomedical and Chemical Sciences, The University of Western Australia, Crawley, Australia.
Matthews
Vance
V
Husk
Kirsten
K
Smyth
Mark J
MJ
Abraham
Lawrence J
LJ
Yeoh
George C
GC
D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D002796:Choline Deficiency; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005001:Ethionine / Q000008:administration & dosage; D006498:Hepatectomy / Q000379:methods; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014947:Wounds and Injuries / Q000503:physiopathology
D004268:DNA-Binding Proteins; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005001:Ethionine