Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance.
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) occurring in the gut of genetically susceptible individuals independent of a specific pathogen. The interaction between antigen-presenting cells and the local bacterial flora contributes to an uncontrolled activation of mucosal CD4+ T lymphocytes with the consecutive release of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6, IL-12, IL-23, IL-27, and also IL-17, which is attributed to a specific, differentiated CD4+ lineage called Th17 (TH-IL17, THi). Recent data suggest that IL-6 contributes to Th17 differentiation. However, to clarify the importance of Th17 cells in IBD further data are needed. So far, CD has been attributed to a Th1-mediated disease, whereas UC exhibits a modified Th2 cytokine response. In both diseases CD4+ T cells at the site of inflammation are critically dependent on antiapoptotic IL-6 signaling. Thereby, IL-6 induces the transcription factor STAT-3 via transsignaling (activation of a cell lacking membrane-bound IL-6 receptor via soluble IL-6 receptor). STAT-3 itself induces the antiapoptotic factors bcl-2 and bcl-xL, thus resulting in T-cell resistance against apoptosis. This vicious circle of T-cell accumulation, mediated by apoptosis resistance, finally leading to chronic inflammation, can be blocked by anti-IL-6 receptor antibodies. This review highlights the role of IL-6 in IBD immunopathogenesis and its clinical relevance in IBD therapy and diagnostics.
Mudter
Jonas
J
1st Medical Clinic, Johannes Gutenberg University of Mainz, Germany. mudter@uni-mainz.de
Neurath
Markus F
MF
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D020381:Interleukin-17 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D020381:Interleukin-17; D015850:Interleukin-6; D019947:Receptors, Interleukin-6