Premium
IL‐4 promotes experimental drug‐induced hepatitis and modulates IP‐10 production
Author(s) -
Njoku Dolores B,
Mellerson Jenelle L,
Sharma Rajni,
Talor Monica Vladut,
Ligons Davinna,
Li Zhaoxia,
Rose Noel R
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a189-c
Subject(s) - splenocyte , cyp2e1 , immune system , hepatitis , hapten , chemistry , autoimmune hepatitis , pharmacology , in vitro , acetaminophen , in vivo , immunology , antibody , medicine , biology , biochemistry , microbiology and biotechnology , microsome
Susceptible persons following administration of halogenated anesthetics or similar drugs, develop immune‐mediated, drug‐induced hepatitis (DIH). Interferon gamma inducible protein (IP‐10) worsens autoimmune or acetaminophen hepatitis, but its role in immune‐mediated DIH is unknown. Using our experimental model of anesthetic DIH created by immunizing mice with liver proteins covalently linked to a TFA hapten (TFA‐S100) formed from CYP2E1 metabolism of anesthetics, we found that baseline splenic IP‐10 levels were significantly higher in IL‐4 deficient (KO) than BALB/c (WT) mice, but WT developed significantly more hepatitis than KO mice. We hypothesize that IL‐4 promotes DIH by reducing IP‐10. To test our hypothesis we analyzed splenocyte cultures stimulated in vitro with CYP2E1 that were obtained from TFA‐S100‐immunized WT and KO mice, as well as from CFA‐immunized WT controls. Splenocyte proliferation was significantly higher in WT than KO mice but IP‐10 levels were significantly higher in KO supernatants. Similarly proliferation was significantly lower in CFA‐ than TFA‐S100‐immunized WT mice but supernatant IP‐10 levels were significantly higher in CFA‐immunized controls, and proliferating cells could not transfer hepatitis to RAG −/− mice. Our findings suggest that IL‐4 promotes immune responses to CYP2E1 in experimental DIH and modulates IP‐10 production. Supported by R21DK075828