Background Administration of granulocyte-macrophage colony stimulating factor (GM-CSF) relieves symptoms in Crohn's disease (CD). It has been reported that reduced GM-CSF bioactivity is associated with more aggressive ileal behaviour and that GM-CSF-null mice exhibit ileal barrier dysfunction and develop a transmural ileitis following exposure to non-steroidal anti-inflammatory drugs (NSAIDs). STAT5 signalling is central to GM-CSF action. It was therefore hypothesised that GM-CSF signalling in non-haematopoietic cells is required for ileal homeostasis.
Methods Bone marrow (BM) chimeras were generated by reconstituting irradiated GM-CSF receptor (gm-csfr) β chain or GM-CSF (gm-csf) deficient mice with wild type BM (WTBM→GMRKO and WTBM→GMKO). Intestinal barrier function and the response to NSAID-induced ileal injury were examined. Expression of gm-csf, gm-csfr or stat5 in Caco-2 and HT-29 intestinal epithelial cell (IEC) lines was knocked down and the effect of GM-CSF signalling on IEC survival and proliferation was determined.
Results Elevated levels of GM-CSF autoantibodies in ileal CD were found to be associated with dysregulation of IEC survival and proliferation. GM-CSF receptor-deficient mice and WTBM→GMRKO chimeras exhibited ileal hyperpermeability. NSAID exposure induced a transmural ileitis in GM-CSF receptor-deficient mice and WTBM→GMRKO chimeras. Transplantation of wild type BM into GM-CSF-deficient mice prevented NSAID ileal injury and restored ileal barrier function. Ileal crypt IEC proliferation was reduced in WTBM→GMRKO chimeras, while STAT5 activation in ileal IEC following NSAID exposure was abrogated in WTBM→GMRKO chimeras. Following knock down of gm-csf, gm-csfr α or β chain or stat5a/b expression in Caco-2 cells, basal proliferation was suppressed. GM-CSF normalised proliferation of Caco-2 cells exposed to NSAID, which was blocked by stat5a/b RNA interference.
Conclusions Loss of GM-CSF signalling in non-haematopoietic cells increases NSAID ileal injury; furthermore, GM-CSF signalling in non-haematopoietic cells regulates ileal epithelial homeostasis via the STAT5 pathway. The therapeutic use of GM-CSF may therefore be beneficial in chronic ileitis associated with CD.
- Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)
- Signals Transducers and Activators of Transcription (STAT5)
- Inflammatory Bowel Disease (IBD)
- Nonsteroidal Anti-inflammatory Drugs
- IBD basic research
- intestinal barrier function
- signal transduction
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Funding Crohns and Colitis Foundation of America (XH), Cincinnati Children's Hospital Research Foundation Digestive Health Center (PHS Grant P30 DK0789392) and Cincinnati Children's Hospital Medical Center Trustee Award (XH). NIH clinical and translational research award KL2 RR026315 (XH).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the Cincinnati Children's Hospital Medical Center, IRB #04-1-10.
Provenance and peer review Not commissioned; externally peer reviewed.