Essential crosstalk between myeloid and lymphoid cells for development of chronic colitis in myeloid-specific signal transducer and activator of transcription 3-deficient mice

Immunology. 2007 Jan;120(1):19-27. doi: 10.1111/j.1365-2567.2006.02473.x.


Dysregulated cytokine responsiveness by myeloid cells can be a trigger for the development of chronic inflammation as well as inflammatory bowel disease. Thus, mice with a myeloid-specific defect in signal transducer and activator of transcription (Stat) 3 develop spontaneous colitis secondary to the inability of myeloid cells to respond to the immunosuppressive cytokine interleukin-10. We now examined whether the inflammation caused by Stat3-deficient macrophages is cell autonomous or dependent on their interaction with lymphocytes. For this purpose, myeloid-specific Stat3-deficient mice (LysMcre/Stat3(flox) mice) were intercrossed with RAG-1 knockout mice to generate LysMcre/Stat3(flox) RAG(-/-) mice. In these mutants and LysMcre/Stat3(flox) littermate control mice we determined the onset and severity of spontaneous chronic enterocolitis, and the reaction to dextran sodium sulphate (DSS)-induced epithelial damage, as well as to lipopolysaccharide (LPS) challenge. In contrast to LysMcre/Stat3(flox) mice, LysMcre/Stat3(flox) RAG(-/-) animals are protected from chronic enterocolitis. Although they respond to oral dextran sulphate with acute colitis symptoms, the inflammation heals similarly to wild type mice whereas LysMcre/Stat3(flox) mice exhibit continued colitis pathology. In addition, the hyperreactivity of LysMcre/Stat3(flox) mice to LPS-challenge in vivo was less severe in the absence of lymphocytes. Despite clear differences in the strength of inflammatory responses, macrophages of both LysMcre/Stat3(flox) mice and LysMcre/Stat3(flox) RAG(-/-) animals exhibited increased costimulatory capacity. In conclusion, our findings demonstrate that Stat3-deficient myeloid cells alone are not capable of inducing the severe pathology seen in LysMcre/Stat3(flox) mice. Yet when these cells can interact with lymphocytes their increased costimulatory potential will trigger an overshooting inflammatory response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • B7-2 Antigen / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Communication / immunology
  • Chronic Disease
  • Cytokines / blood
  • Dextran Sulfate
  • Enterocolitis / chemically induced
  • Enterocolitis / immunology*
  • Enterocolitis / pathology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology
  • Lipopolysaccharides / immunology
  • Lymphocytes / immunology*
  • Macrophages / immunology*
  • Mice
  • Mice, Knockout
  • STAT3 Transcription Factor / deficiency
  • STAT3 Transcription Factor / immunology*
  • Weight Gain / immunology


  • B7-2 Antigen
  • Cytokines
  • Homeodomain Proteins
  • Lipopolysaccharides
  • STAT3 Transcription Factor
  • RAG-1 protein
  • Dextran Sulfate