| First Author | Rani R | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 48 | Pages | 18466-18476 |
| PubMed ID | 30348900 | Mgi Jnum | J:272880 |
| Mgi Id | MGI:6268628 | Doi | 10.1074/jbc.RA118.005583 |
| Citation | Rani R, et al. (2018) Mechanisms of concanavalin A-induced cytokine synthesis by hepatic stellate cells: Distinct roles of interferon regulatory factor-1 in liver injury. J Biol Chem 293(48):18466-18476 |
| abstractText | Mice depleted of hepatic stellate cells (HSCs) are protected from concanavalin A (ConA)-induced liver injury that is mediated by the activation of interferon regulatory factor 1 (IRF1). The aim of this study was to determine the mechanisms of ConA-mediated signaling and synthesis/release of mediators by HSCs that damage hepatocytes. Primary cultures of wildtype (WT) and IRF1-knockout (KO) HSCs and hepatocytes were used, and ConA-induced liver damage in interferon (IFN)alphabeta receptor-deficient (IFNalphabetaR-KO) mice was determined. Specific binding of ConA to HSCs induced rapid activation of JAK2 and STAT1. ConA-induced expression of IRF1, IFNbeta, tumor necrosis factor alpha, and CXCL1 was abrogated by selective inhibition of JAK2 and STAT1. Despite activating JAK2/STAT1, ConA failed to stimulate expression of inflammatory cytokines in HSCs from IRF1-KO mice. ConA-conditioned WT-HSC medium caused activation of JNK and caspase 3, and apoptosis of hepatocytes from WT but not from IRF1-KO or IFNalphabetaR-KO mice. Conversely, ConA-conditioned medium of IRF1-KO HSCs failed to cause apoptosis of WT or IRF1-KO hepatocytes. IFNalphabetaR-KO mice were protected from ConA-induced liver damage, and ConA-induced hepatic expression of IRF1 and pro-inflammatory cytokines and chemokines, and infiltration of neutrophils were significantly lower in IFNalphabetaR-KO than in WT mice. These results demonstrate distinct roles of IRF1 in hepatic inflammation (HSCs) and injury (hepatocytes) and can be an important target for intervention in acute liver injury. |
