Interleukin-6 trans-signaling and colonic cancer associated with inflammatory bowel disease

Stefan Rose-John, Keiichi Mitsuyama, Satoshi Matsumoto, Wolfgang M Thaiss, Jürgen Scheller
Current Pharmaceutical Design 2009, 15 (18): 2095-103
The complex pathogenesis of inflammatory bowel disease (IBD) and inflammation induced colon cancer involves a wide range of mediators including cytokines. Recent investigations underline the fundamental role of interleukin-6 (IL-6) signaling in the development and maintenance of IBD and for the progression of this inflammation to colon cancer. The molecular mechanisms of this pathway, the source of the cytokine and the identity of target cells in the intestine are incompletely understood. It is known that the circulating and intestinal levels of IL-6 as well as the soluble IL-6 receptor (sIL-6R) are increased in patients with IBD. Remarkably, mucosal T cells of IBD patients are extremely resistant to apoptosis and a large fraction of these cells express membrane-bound gp130 but not the IL-6R. Increasing evidence suggests that the development and perpetuation of IBD relies on IL-6 synthesized by T-cells and myeloid cells and on increased formation of IL-6/sIL-6R complexes interacting with membrane-bound gp130 on T-cells, a process called IL-6 trans-signaling. Recent investigations suggested a protective role of IL-6 mediated STAT3 signaling in intestinal epithelial cells. Here we review these pro- and anti-inflammatory properties of IL-6 in IBD and inflammation induced colon cancer and we will summarize the consequences of these new results for the prospects of IL-6 targeted therapeutic strategies for the treatment of chronic inflammatory diseases such as IBD.

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