Deficiency of Interleukin-15 Enhances Susceptibility to Acetaminophen-Induced Liver Injury in Mice

Hsein-San Hou, Ching-Len Liao, Huey-Kang Sytwu, Nan-Shih Liao, Tien-Yu Huang, Tsai-Yuan Hsieh, Heng-Cheng Chu

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8 Citations (Scopus)

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. © 2012 Hou et al.
Original languageEnglish
JournalPLoS One
Volume7
Issue number9
DOIs
Publication statusPublished - 2012
Externally publishedYes

Keywords

  • galactosamine
  • gamma interferon
  • glutathione
  • heme oxygenase 1
  • inducible nitric oxide synthase
  • interleukin 15
  • interleukin 1beta
  • paracetamol
  • recombinant interleukin 15
  • tumor necrosis factor alpha
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • article
  • cell infiltration
  • cell transport
  • controlled study
  • cytokine production
  • disease predisposition
  • drug metabolism
  • knockout mouse
  • Kupffer cell
  • liver cell
  • male
  • monocyte
  • mouse
  • neutrophil
  • nonhuman
  • protein blood level
  • protein deficiency
  • survival
  • toxic hepatitis
  • wild type
  • Acetaminophen
  • Animals
  • Antibodies, Neutralizing
  • Disease Susceptibility
  • Dose-Response Relationship, Drug
  • Drug-Induced Liver Injury
  • Enzyme Induction
  • Gene Knockout Techniques
  • Heme Oxygenase-1
  • Hepatitis
  • Interleukin-15
  • Kupffer Cells
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase Type II
  • Organ Specificity
  • Recombinant Proteins
  • Transcription, Genetic
  • Animalia
  • Mus

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    Hou, H-S., Liao, C-L., Sytwu, H-K., Liao, N-S., Huang, T-Y., Hsieh, T-Y., & Chu, H-C. (2012). Deficiency of Interleukin-15 Enhances Susceptibility to Acetaminophen-Induced Liver Injury in Mice. PLoS One, 7(9). https://doi.org/10.1371/journal.pone.0044880