A non-hepatotropic parasite infection increases mortality in the acetaminophen-induced acute liver failure murine model: possible roles for IL-5 and IL-6

Abstract

We evaluated the effects of a non-hepatotropic parasite infection (Taenia crassiceps) on the outcome of acetaminophen-induced acute liver failure in mice. Uninfected and T. crassiceps infected mice orally received either 300 mg/kg acetaminophen or water as vehicle (n = 5 per group). Survival analysis, hepatocyte necrosis, alanine aminotransferase (ALT) levels, CYP2E1 protein, interleukin (IL-) 5, and IL-6 were assessed for all groups. All infected mice died within 16 h after exposure to acetaminophen (Tc+APAP group), whereas only one-third of uninfected animals exposed to acetaminophen (APAP group) died. Uninfected (Control group) and infected (Tc group) mice that received the vehicle showed no liver damage. Tc+APAP mice exhibited massive liver necrosis characterised by marked balloning degeneration of hepatocytes and higher serum ALT compared to Control, Tc, and APAP animals. Liver tissue from Tc+APAP mice also displayed increased expression of CYP2E1 protein and higher mRNA and protein levels of IL-5 and IL-6 compared to the other groups. These findings suggest that non-hepatotropic parasite infections may increase mortality following acute liver failure by promoting hepatocyte necrosis via IL-5 and IL-6-dependent CYP2E1 overproduction. This study identifies new potential risk factors associated with severe acute liver failure in patients.

The immunological mechanisms and therapeutic potential in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity

“…IL-5 is a Th2 cytokine that has been confirmed to be associated with increased liver injury in hepatitis induced by lipopolysaccharide and concanavalin A. Only a few articles reported that APAP increases IL-5 expression in mouse liver [ 208 , 209 ]. Ginsenoside Rg3 reduces some inflammatory factors, including IL-5, and alleviates APAP hepatotoxicity [ 208 ].…”

“…Ginsenoside Rg3 reduces some inflammatory factors, including IL-5, and alleviates APAP hepatotoxicity [ 208 ]. De León-Nava et al do not find leukocytes infiltration in the liver parenchyma during APAP-induced ALF, probably because IL-5 causes liver injury in a leukocyte-independent manner or that IL-5 expression is an indirect consequence of liver injury and has no effect on pathology [ 209 ]. Researchers examined the expression of 40 cytokines in APAP-induced hepatotoxicity model mice and showed that APAP increases tenfold levels of IL-1α, IL-7, IL-17, CCL1, CCL3, CCL4, macrophage colony-stimulating factor (M-CSF) and CXCL9.…”