Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer.
Inflammatory bowel disease (IBD), which consists of Crohn's disease and ulcerative colitis, is defined as a chronic inflammation of the gastrointestinal tract. The etiopathogenetic mechanisms underlying the development of IBD are still not completely understood, and the therapeutic strategies used thus far have been limited to mostly evidence-based principles. There is growing evidence that the pro-inflammatory cytokine interleukin (IL)-6 plays a crucial part in the uncontrolled intestinal inflammatory process, which is a main characteristic of IBD. There is elevated production of IL-6 and its soluble receptor (sIL-6R) by intestinal macrophages and CD4+T-cells. The increased formation of IL-6-sIL-6R complexes that interact with gp130 on the membrane of CD4+T-cells (trans-signaling) lead to an increased expression and nuclear translocation of STAT3, which causes the induction of anti-apoptotic genes, such as Bcl-xl. This leads to an augmented resistance of lamina propria T-cells to apoptosis. The ensuing T-cell expansion contributes to the perpetuation of chronic intestinal inflammation. This understanding concerning the predominant pathogenic role of an IL-6-dependent inflammatory cascade may lead to the development of new therapeutic strategies in the treatment of this disease. Recent studies have also suggested a potential role of IL-6-sIL-6R in the pathogenesis of colon cancer and, therefore, imply a possible novel therapeutic strategy targeting the sIL-6R and ensuing IL-6 trans-signaling.
Atreya
Raja
R
Laboratory of Immunology, I. Medical Clinic, University of Mainz, 55131 Mainz, Germany. neurath@1-med.klinik.unimainz.de
Neurath
Markus F
MF
D000818:Animals; D015179:Colorectal Neoplasms / Q000276:immunology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology*
D015850:Interleukin-6