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 mucsosa 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. (C) 2004 Elsevier Ltd. All rights reserved.