title: Deficiency of interleukin-15 enhances susceptibility to acetaminophen-induced liver injury in mice.
abstract: Hepatocytes have a direct necrotic role in acetaminophen (APAP)-induced liver injury (AILI), prolonged secondary inflammatory response through innate immune cells and cytokines also significantly contributes to APAP hepatotoxicity. Interleukin 15 (IL-15), a multifunction cytokine, regulates the adaptive immune system and influences development and function of innate immune cells. To better understand the role of IL-15 in liver injury, we treated wild-type (WT) and IL-15-knockout (Il15⁻/⁻) mice with a hepatotoxic dose of APAP to induce AILI and evaluated animal survival, liver damage, APAP metabolism in livers and the inflammatory response. Production of pro-inflammatory cytokines/chemokines was greater in Il15⁻/⁻ than WT mice. Subanalysis of hepatic infiltrated monocytes revealed greater neutrophil influx, along with greater hepatic induction of inducible nitric oxide synthase (iNOS), in Il15⁻/⁻ than WT mice. In addition, the level of hepatic hemeoxygenase 1 (HO-1) was partially suppressed in Il15⁻/⁻ mice, but not in WT mice. Interestingly, elimination of Kupffer cells and neutrophils did not alter the vulnerability to excess APAP in Il15⁻/⁻ mice. However, injection of galactosamine, a hepatic transcription inhibitor, significantly reduced the increased APAP sensitivity in Il15⁻/⁻ mice but had minor effect on WT mice. We demonstrated that deficiency of IL-15 increased mouse susceptibility to AILI. Moreover, Kupffer cell might affect APAP hepatotoxicity through IL-15.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Hsein-San
authors.initials: HS
authors.lastname: Hou
authors.forename: Ching-Len
authors.initials: CL
authors.lastname: Liao
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
authors.forename: Nan-Shih
authors.initials: NS
authors.lastname: Liao
authors.forename: Tien-Yu
authors.initials: TY
authors.lastname: Huang
authors.forename: Tsai-Yuan
authors.initials: TY
authors.lastname: Hsieh
authors.forename: Heng-Cheng
authors.initials: HC
authors.lastname: Chu
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D055786:Gene Knockout Techniques; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006505:Hepatitis / Q000201:enzymology / Q000209:etiology; D019409:Interleukin-15 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009928:Organ Specificity; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D057134:Antibodies, Neutralizing; D019409:Interleukin-15; D011994:Recombinant Proteins; D000082:Acetaminophen; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1