Growth Hormone Stops Excessive Inflammation After Partial Hepatectomy, Allowing Liver Regeneration and Survival Through Induction of H2‐Bl/HLA‐G

BACKGROUND AND AIMS: Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. APPROACH AND RESULTS: PHx was performed on C57BL/6 mice lacking GHR (Ghr (−/−)), disabled for all GH‐dependent Janus kinase 2 signaling (Box1 (−/−)), or lacking only GH‐dependent signal transducer and activator of transcription 5 (STAT5) signaling (Ghr391 (−/−)), and wild‐type littermates. C57BL/6 Ghr (−/−)mice showed striking mortality within 48 hours after PHx, whereas Box1 (−/−) or Ghr391 (−/−) mice survived with normal liver regeneration. Ghr (−/−) mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2‐Bl, a key immunotolerance protein, which is up‐regulated by PHx through a GH‐mediated, Janus kinase 2–independent, SRC family kinase–dependent pathway. GH treatment was confirmed to up‐regulate expression of the human homolog of H2‐Bl (human leukocyte antigen G [HLA‐G]) in primary human hepatocytes and in the serum of GH‐deficient patients. We find that injury‐associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the 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. Further, H2‐Bl knockdown in wild‐type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr (−/−) backcrossed on a strain with high endogenous H2‐Bl expression showed a high rate of survival following PHx. CONCLUSIONS: GH induction of H2‐Bl expression is crucial for reducing innate immune‐mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA‐G may lead to improved clinical outcomes following liver surgery or transplantation.