Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury
Anissa A. Widjaja, Jinrui Dong, Eleonora Adami, Sivakumar Viswanathan, Benjamin Ng, Leroy Sivappiragasam Pakkiri, Sonia Chothani, Brijesh Kumar Singh, Wei‐Wen Lim, Jin Zhou, Shamini G. Shekeran, Jessie Tan, Sze Yun Lim, Joyce Wei Ting Goh, Mao Wang, Robert Holgate, Arron Hearn, Leanne E. Felkin, Paul M. Yen, James W. Dear, Chester Lee Drum, Sebastian Schäfer, Stuart A. Cook
Abstract
was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.