Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3

Cell Immunol. 2011;268(1):37-46. doi: 10.1016/j.cellimm.2011.01.008. Epub 2011 Feb 4.


The aim of this study was to delineate the temporal and spatial sequence of STAT1 and STAT3 activation during development of GVHD following fully Major Histocompatibility Complex (MHC)-mismatched allogeneic Bone Marrow Transplantation (BMT). Activation of inflammatory signaling pathways in GVHD target organs was assessed by western blotting, phospho-flow cytometry and electromobility shift assays (EMSA). Development of GVHD was associated with significant expansion of phospho[p]-STAT1 and p-STAT3 expressing CD4(+) T cells and CD8(+) T cells. GVHD-specific STAT3/STAT1 activation preceded activation of Nuclear Factor-κB (NF-κB) and Mitogen Activated Protein Kinase (MAPK) and was associated with subsequent induction of STAT1 or STAT3-dependent inflammatory gene-expression programs (e.g. expression of IRF-1, SOCS1, IL-17). Our studies may help to establish a functional hierarchy of the signaling events leading to the development of GVHD and could be helpful in designing new molecularly targeted treatment approaches for GVHD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enzyme Activation / immunology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Graft vs Host Disease / immunology*
  • Inflammation*
  • Liver / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase Kinases / immunology
  • NF-kappa B / immunology
  • STAT1 Transcription Factor / immunology*
  • STAT3 Transcription Factor / immunology*
  • Signal Transduction*
  • Spleen / enzymology
  • Spleen / immunology
  • T-Lymphocytes / immunology
  • Th17 Cells / immunology


  • NF-kappa B
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • Mitogen-Activated Protein Kinase Kinases