In drug-induced, immune-mediated hepatitis, interleukin-33 reduces hepatitis and improves survival independently and as a consequence of FoxP3+ T-cell activity

Immune-mediated,drug-induced hepatitis is a rare complication of halogenated volatile anesthetic administration.IL-4-regulated Th2-polarized reactions initiate this type and other types of hepatitis,while the mechanisms that regulate the severity remain elusive.IL-33 is an innate,IL-4-inducing,Th2-polarizing cytokine that has been detected in patients with liver failure and has been associated with upregulated ST2+Foxp3+CD4+CD25+T cells;however,roles for IL-33 in drug-induced hepatitis are unclear.We investigated IL-33 in an anesthetic,immune-mediated hepatitis modeled in BALB/c,IL-33−/−and ST2−/−mice,as well as in patients with anesthetic hepatitis.The hepatic IL-33 and ST2 levels were elevated in BALB/c mice(p<0.05)with hepatitis,and anti-IL-33 diminished hepatitis(p<0.05)without reducing IL-33 levels.The complete absence of IL-33 reduced IL-10(p<0.05)and ST2+Foxp3+CD4+CD25+T cells(p<0.05),as well as reduced the overall survival(p<0.05),suggesting suppressive roles for IL-33 in anesthetic,immune-mediated hepatitis.All of the mice demonstrated similar levels of CD4+T-cell proliferation following direct Tcell receptor stimulation,but we detected splenic IL-33 and ST2-negative Foxp3+CD4+CD25+T cells in ST2−/−mice that developed less hepatitis than BALB/c mice(p<0.05),suggesting that ST2-negative Foxp3+CD4+CD25+T cells reduced hepatitis.In patients,serum IL-33 and IPEX levels were correlated in controls(r2=0.5,p<0.05),similar to the levels in mice,but not in anesthetic hepatitis patients(r2=0.01),who had elevated IL-33(p<0.001)and decreased IPEX(p<0.01).Our results suggest that,in anesthetic,immune-mediated hepatitis,IL-33 does not regulate the CD4+T-cell proliferation that initiates hepatitis,but IL-33,likely independent of ST2,reduces hepatitis via upregulation of Foxp3+CD4+CD25+T cells.Further studies are needed to translate the role of IL-33 to human liver disease.