TY - JOUR
T1 - The regulatory role of PGC1α-related coactivator in response to drug-induced liver injury
AU - Buler, Marcin
AU - Naessens, Thomas
AU - Mattsson, Johan
AU - Morias, Yannick
AU - Söderberg, Magnus
AU - Robbins, Philip
AU - Kärrberg, Lillevi
AU - Svensson, Tor S.
AU - Thulin, Petra
AU - Glinghammar, Björn
AU - Scarpulla, Richard C.
AU - Andersson, Ulf
N1 - Publisher Copyright:
© 2020 The Authors. FASEB BioAdvances published by the Federation of American Societies for Experimental Biology
PY - 2020/8
Y1 - 2020/8
N2 - PGC1α-Related Coactivator (PRC) is a transcriptional coactivator promoting cytokine expression in vitro in response to mitochondrial injury and oxidative stress, however, its physiological role has remained elusive. Herein we investigate aspects of the immune response function of PRC, first in an in vivo thioacetamide (TAA)-induced mouse model of drug-induced liver injury (DILI), and subsequently in vitro in human monocytes, HepG2, and dendritic (DC) cells. TAA treatment resulted in the dose-dependent induction of PRC mRNA and protein, both of which were shown to correlate with liver injury markers. Conversely, an adenovirus-mediated knockdown of PRC attenuated this response, thereby reducing hepatic cytokine mRNA expression and monocyte infiltration. Subsequent in vitro studies with conditioned media from HepG2 cells overexpressing PRC, activated human monocytes and monocyte-derived DC, demonstrated up to 20% elevated expression of CD86, CD40, and HLA-DR. Similarly, siRNA-mediated knockdown of PRC abolished this response in oligomycin stressed HepG2 cells. A putative mechanism was suggested by the co-immunoprecipitation of Signal Transducer and Activator of Transcription 1 (STAT1) with PRC, and induction of a STAT-dependent reporter. Furthermore, PRC co-activated an NF-κB-dependent reporter, indicating interaction with known major inflammatory factors. In summary, our study indicates PRC as a novel factor modulating inflammation in DILI.
AB - PGC1α-Related Coactivator (PRC) is a transcriptional coactivator promoting cytokine expression in vitro in response to mitochondrial injury and oxidative stress, however, its physiological role has remained elusive. Herein we investigate aspects of the immune response function of PRC, first in an in vivo thioacetamide (TAA)-induced mouse model of drug-induced liver injury (DILI), and subsequently in vitro in human monocytes, HepG2, and dendritic (DC) cells. TAA treatment resulted in the dose-dependent induction of PRC mRNA and protein, both of which were shown to correlate with liver injury markers. Conversely, an adenovirus-mediated knockdown of PRC attenuated this response, thereby reducing hepatic cytokine mRNA expression and monocyte infiltration. Subsequent in vitro studies with conditioned media from HepG2 cells overexpressing PRC, activated human monocytes and monocyte-derived DC, demonstrated up to 20% elevated expression of CD86, CD40, and HLA-DR. Similarly, siRNA-mediated knockdown of PRC abolished this response in oligomycin stressed HepG2 cells. A putative mechanism was suggested by the co-immunoprecipitation of Signal Transducer and Activator of Transcription 1 (STAT1) with PRC, and induction of a STAT-dependent reporter. Furthermore, PRC co-activated an NF-κB-dependent reporter, indicating interaction with known major inflammatory factors. In summary, our study indicates PRC as a novel factor modulating inflammation in DILI.
KW - PPRC1
KW - PRC
KW - cytokine expression
KW - drug-induced liver injury
KW - hepatic inflammation
UR - http://www.scopus.com/inward/record.url?scp=85106261242&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85106261242&partnerID=8YFLogxK
U2 - 10.1096/fba.2020-00003
DO - 10.1096/fba.2020-00003
M3 - Article
C2 - 32821877
AN - SCOPUS:85106261242
SN - 2573-9832
VL - 2
SP - 453
EP - 463
JO - FASEB BioAdvances
JF - FASEB BioAdvances
IS - 8
ER -