title: Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice.
abstract: Interleukin-15 (IL-15) and its high affinity receptor interleukin-15 receptor alpha (IL-15Rα) are widely expressed in immune cells and hepatic resident cells. IL-15 signaling has important functions in homeostasis of natural killer (NK), natural killer T (NKT) and cytotoxic T (CD8(+) T) cells, and in liver regeneration. We hypothesized that IL-15 has a protective role in liver fibrosis progression by maintaining NK cell homeostasis.
  
  
  
  Fibrosis was induced using two mechanistically distinct models. Congenic bone marrow transplantation was used to evaluate the contribution of IL-15 signaling from various compartments to NK, CD8(+) T and NKT cell homeostasis and fibrogenesis. The gene expression profile of hepatic stellate cell (HSC) from IL-15Rα knockout (IL-15RαKO) mice and wild-type mice were captured using microarray analysis and validated in isolated HSC. Quantitative real-time PCR was used to assess repressors of collagen transcription.
  
  
  
  IL-15RαKO mice exhibited more fibrosis in both models. IL-15 signaling from specific types of hepatic cells had divergent roles in maintaining liver NK, CD8(+) T and NKT cells, with a direct and protective role on radio-resistant non-parenchymal cells beyond the control of NK homeostasis. HSCs isolated from IL-15RαKO mice demonstrated upregulation of collagen production. Finally, IL-15RαKO HSC with or without transforming growth factor beta (TGF-β) stimulation exhibited increased expression of fibrosis markers and decreased collagen transcription repressors expression.
  
  
  
  IL-15Rα signaling has a direct anti-fibrotic effect independent of preserving NK homeostasis. These findings establish a rationale to further explore the anti-fibrotic potential of enhancing IL-15 signaling in HSCs.
  
  
  
  We investigated how a cellular protein, Interleukin-15 (IL-15), decreases the amount of scar tissue that is formed upon liver injury. We found that IL-15 and its receptor decrease the amount of scar tissue that is created by specialized liver cells (called stellate cells) and increase the number of a specific subgroup of immune cells (natural killer cells) that are known to eliminate stellate cells.
  
  
  
  GSE45612, GSE 68001 and GSE 25097.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Ooka
authors.affiliation: Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Fey
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Fiel
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Adeeb H
authors.initials: AH
authors.lastname: Rahmman
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Xintong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: de Paula
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Vetter
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sastre
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ka Hin
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Youngmin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Meena
authors.initials: M
authors.lastname: Bansal
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL, USA.|Division of Digestive Diseases, Rush University, Chicago, IL, USA.
authors.forename: Costica
authors.initials: C
authors.lastname: Aloman
mesh_terms: D000818:Animals; D055166:Hepatic Stellate Cells; D019409:Interleukin-15; D008103:Liver Cirrhosis; D051379:Mice; D008810:Mice, Inbred C57BL; D053647:Receptors, Interleukin-15
chemical_list: C508025:Il15ra protein, mouse; D019409:Interleukin-15; D053647:Receptors, Interleukin-15
keywords: Collagen; Fibrosis; Hepatic stellate cells; Interleukin 15; Mice; NK cells; NKT cells