Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis.
We have generated mice in which the gene encoding the transcription factor STAT3 can be inactivated in multiple cell types by triggering the endogenous production of type I interferon. Gene inactivation is particularly effective in the liver and the adipose tissue, as well as in macrophages and gut epithelial cells. Upon induction of the mutation, mice develop a wasting syndrome culminating in an aggressive and fatal form of enterocolitis, limited to the large intestine, within 2-3 weeks after the treatment. The disease is characterised by massive infiltration of the gut mucosa by macrophages, granulocytes and CD4+ cells, increased expression of endothelial adhesion molecules and high production of the cytokines interleukin (IL)-6, IL-12, interferon-gamma and IL-10. IL-12 p40 plays a pivotal role in disease development as in vivo treatment with neutralising antibodies completely prevents its onset. Interestingly, oral treatment with wide spectrum antibiotics does not have any effect on either the onset or the development of colitis. Taken together, these data show that STAT3 plays a crucial role in the maintenance of intestinal homeostasis and possibly in mediating specialised cell functions in the intestinal epithelium.
Alonzi
Tonino
T
National Institute for Infectious Disease L. Spallanzani IRCCS, Via Portuense 292, 00149 Rome, Italy. alonzi@inmi.it
Newton
Ian P
IP
Bryce
Paul J
PJ
Di Carlo
Emma
E
Lattanzio
Giuseppe
G
Tripodi
Marco
M
Musiani
Piero
P
Poli
Valeria
V
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use; D003106:Colon / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004760:Enterocolitis / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D017353:Gene Deletion; D018664:Interleukin-12 / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D019282:Wasting Syndrome / Q000209:etiology / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000906:Antibodies; D016207:Cytokines; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12