| Autor: |
Dong J; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Lim WW; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169857, Singapore., Shekeran SG; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Tan J; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169857, Singapore., Lim SY; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Goh JWT; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., George BL; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Schafer S; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Cook SA; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169857, Singapore.; MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK., Widjaja AA; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore. |
| Abstrakt: |
N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11/IL11RA/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKO Il11 ) or gp130 (CKO gp130 ) in adult hepatocytes. Following APAP, as compared to controls, CKO gp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKO gp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKO Il11 mice that, as compared to wild-type mice, had lower APAP-induced ALT/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKO gp130 mice, APAP-treated CKO Il11 mice had lesser ERK/JNK/NOX4 activation and greater features of regeneration. Both CKO gp130 and CKO Il11 mice had normal APAP metabolism. After APAP, CKO gp130 and CKO Il11 mice had reduced Il6 , Ccl2 , Ccl5 , Il1β , and Tnfα expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative. |
