The therapeutic utility of Interleukin-11 in the treatment of inflammatory disease.
Interleukin-11 (IL-11) is a pleiotropic cytokine that exhibits anti-inflammatory and mucosal protective effects in a variety of animal models of acute and chronic inflammation, such as mucositis, inflammatory bowel disease and autoimmune joint disease. This reduction in inflammation and epithelial damage is mediated in part through effects of recombinant human (rh) IL-11 on macrophage effector function and epithelial cell growth. In vitro studies indicate that rhIL-11 inhibits tumour necrosis factor (TNF)-alpha, IL-1beta, IL-12, IL-6, and nitric oxide production from activated macrophages. Analysis of the effects of rhIL-11 on transcription factors that activate pro-inflammatory cytokines demonstrate that the level of induced nuclear factor kappa B (NF-kappaB) binding activity in the nucleus of rhIL-11-treated peritoneal macrophages is significantly reduced. Studies of normal intestinal epithelial cells indicate that rhIL-11 reduces the rate of cellular proliferation. Analysis of cell-cycle progression demonstrates that growth inhibition of epithelial cells by rhIL-11 correlates with delayed entry into S phase and suppression of pRB phosphorylation. IL-11 also protects intestinal crypt stem cells from radiation- or chemotherapy-induced insults. Such immunomodulatory and epithelial activities may contribute to the protective effects of this cytokine and support the clinical utility of rhIL-11 in the treatment of mucositis, as well as a variety of chronic inflammatory diseases, such as Crohn's disease and rheumatoid arthritis.
Department of Preclinical Molecular and Cellular Biology, Genetics Institute, Andover, MA 01810, USA.
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Trepicchio
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Dorner