Growth hormone induction of the immunotolerance gene H2- Bl/HLA-G is essential for survival after partial hepatectomy

M Ishikawa1,2, AJ Brooks1,3, MA Fernández-Rojo1,4,5, Y Chhabra1,3, S Minami2, RG Parton1, JP Vivian6,7, J Rossjohn6,7,8, KKY Ho9 and MJ Waters1

  1. The University of Queensland, Institute for Molecular Bioscience, Qld 4072, Australia
  2. Center for Endocrinology, Diabetes and Arteriosclerosis, Nippon Medical School Musashikosugi Hospital, Kawasaki 211-8533, Japan
  3. The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Qld 4072, Australia
  4. Hepatic Fibrosis Group, The Queensland Institute of Medical Research, Brisbane, Queensland, Australia
  5. School of Medicine, The University of Queensland, Herston, 4006, Brisbane, Australia
  6. Monash University, Department of Biochemistry and Molecular Biology School of Biomedical Sciences Building 77, VIC 3800, Australia
  7. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia
  8. Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
  9. School of Medicine, University of Queensland, Herston, Queensland, Australia

Liver regeneration after partial hepatectomy is growth hormone (GH) dependent in rodents, and in C57BL/6 mice, we show that this is a consequence of induction of the potent immunosuppressive protein H2-Bl (homologue of HLA-G in human). We investigated partial hepatectomy in C57BL/6 mice harbouring different GH receptor (GHR) knockin mutants which delete key signalling domains. Striking mortality post-hepatectomy was evident only in mice lacking GH receptor (Ghr-/-), while GHR knockin mice disabled for all GH-dependent JAK2 signalling (Box1-/-), or for GH-dependent STAT5 signalling (Ghr391-/-), showed minimal mortality. Ghr-/- mortality was associated with decreased phospho-JUN expression, and increased apoptosis with elevated NK/NKT and macrophage cell markers. We had identified a set of GH-regulated genes triggered by a novel SRC pathway independent of JAK2, and within this set the Ghr-/- mice exhibited sharply decreased expression of H2-Bl, a key immunotolerance molecule that acts on the inhibitory receptors ILT2 and ILT4. We show H2-Bl is GH regulated in AML12 hepatocyte cells via SRC/JUN. We find that injury-associated innate immune attack by NK/NKT and macrophage cells is instrumental in failure of liver regeneration, and this can be overcome in Ghr-/- mice by adenoviral delivery of H2-Bl or by infusion of HLA-G protein. We identified that GH treatment of GH deficient patients’ results in increased serum HLA-G. Our studies show that GH upregulation of H2-Bl reduces innate immune-mediated apoptosis after partial hepatectomy.