Jingjing Jiao1, Kohtaro Ooka2, Holger Fey3, Maria Isabel Fiel4, Adeeb H Rahmman5, Kensuke Kojima5, Yujin Hoshida5, Xintong Chen5, Tatiana de Paula5, Diana Vetter5, David Sastre5, Ka Hin Lee5, Youngmin Lee5, Meena Bansal5, Scott L Friedman5, Miriam Merad6, Costica Aloman3,7. 1. Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2. Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. 3. Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL, USA. 4. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 5. Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 6. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 7. Division of Digestive Diseases, Rush University, Chicago, IL, USA.
Abstract
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LAY SUMMARY: 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. TRANSCRIPT PROFILING ACCESSION NUMBER: GSE45612, GSE 68001 and GSE 25097.
BACKGROUND & AIMS: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. METHODS: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. RESULTS: 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. CONCLUSIONS: 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. LAY SUMMARY: 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. TRANSCRIPT PROFILING ACCESSION NUMBER: GSE45612, GSE 68001 and GSE 25097.
Authors: Aravind Subramanian; Pablo Tamayo; Vamsi K Mootha; Sayan Mukherjee; Benjamin L Ebert; Michael A Gillette; Amanda Paulovich; Scott L Pomeroy; Todd R Golub; Eric S Lander; Jill P Mesirov Journal: Proc Natl Acad Sci U S A Date: 2005-09-30 Impact factor: 11.205
Authors: A Arina; O Murillo; J Dubrot; A Azpilikueta; I Gabari; J L Perez-Gracia; C Alfaro; C Berasain; J Prieto; S Ferrini; S Hervas-Stubbs; I Melero Journal: Gene Ther Date: 2008-02-14 Impact factor: 5.250
Authors: Nicholas D Huntington; Hamsa Puthalakath; Priscilla Gunn; Edwina Naik; Ewa M Michalak; Mark J Smyth; Hyacinth Tabarias; Mariapia A Degli-Esposti; Grant Dewson; Simon N Willis; Noboru Motoyama; David C S Huang; Stephen L Nutt; David M Tarlinton; Andreas Strasser Journal: Nat Immunol Date: 2007-07-08 Impact factor: 25.606
Authors: Rifaat Safadi; Masayuki Ohta; Carlos E Alvarez; M Isabel Fiel; Meena Bansal; Wajahat Z Mehal; Scott L Friedman Journal: Gastroenterology Date: 2004-09 Impact factor: 22.682
Authors: Manush Saydmohammed; Anupma Jha; Vineet Mahajan; Dillon Gavlock; Tong Ying Shun; Richard DeBiasio; Daniel Lefever; Xiang Li; Celeste Reese; Erin E Kershaw; Vijay Yechoor; Jaideep Behari; Alejandro Soto-Gutierrez; Larry Vernetti; Andrew Stern; Albert Gough; Mark T Miedel; D Lansing Taylor Journal: Exp Biol Med (Maywood) Date: 2021-05-06
Authors: Zhou Zhou; Ming-Jiang Xu; Yan Cai; Wei Wang; Joy X Jiang; Zoltan V Varga; Dechun Feng; Pal Pacher; George Kunos; Natalie J Torok; Bin Gao Journal: Cell Mol Gastroenterol Hepatol Date: 2018-01-08