New insights on fibrosis in Crohn's disease

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Publisher: Expert Reviews Ltd.
Document Type: Report
Length: 2,306 words
Lexile Measure: 1480L

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Author(s): Jennifer R Bailey [*] 1 , Christine V Whiting 2 , John F Tarlton 3 , Paul W Bland 4 , Christopher SJ Probert 5



collagen; Crohn's disease; extracellular matrix; fibrosis; inflammation

Crohn's disease results from a dysregulated immune response in a susceptible individual. Although the inflammation can be controlled, recurrent relapses and chronicity have consequences which are not responsive to current therapies. In particular, the development of fibrotic strictures requiring surgical excision is a debilitating complication of the disease, with around 60% of Crohn's disease sufferers undergoing surgery at least once in the 20 years following their initial diagnosis [1] . Fibrosis occurs owing to excessive deposition of extracellular matrix (ECM), particularly fibrous collagen, and dysregulated ECM turnover [2,3] ; the subsequent hardening and thickening of the tissue lead to a loss of function.

Fibrogenesis is a multifactorial process and it is not known how or why fibrosis develops in such a high proportion of Crohn's disease patients. Cytokines involved in the inflammatory process have long been known to play a role in the development of fibrosis; in particular, the regulatory cytokine TGF-[beta] and co-expressed connective tissue growth factor have been shown to have a number of profibrotic effects, such as recruiting ECM-producing cells and increasing collagen synthesis in several organs, including lung, liver and kidney, as well as intestine [4] . TNF-[alpha], a proinflammatory cytokine which has dominated research and development of biological therapies for Crohn's disease in recent years, is also implicated in fibrogenesis [5] . Similar to TGF-[beta], it upregulates collagen accumulation and stimulates proliferation of myofibroblasts; furthermore, it exacerbates the inflammatory response, increasing synthesis of IL-1[beta] and IL-6, also capable of driving fibrosis [4] . Recent research has found that the Th2 cytokine, IL-13, is present at increased levels in fibrotic Crohn's intestine [2] . This cytokine has been implicated in the development of fibrosis in lung, liver and kidney and has been shown to act in synergy with TNF-like weak inducer of apoptosis to promote fibroblast proliferation in a mouse model of colitis [6] . In 2006, Fichtner-Feigl et al . described a two-step mechanism whereby IL-13 contributed to fibrogenesis by inducing TGF-[beta] synthesis in macrophages [7] . Two receptors exist for IL-13; the primary receptor IL-13R[alpha]1 and IL-13R[alpha]2, which was originally thought to be a decoy receptor but is now known to be significant in IL-13 profibrotic signalling. In the presence of TNF-[alpha], IL-13 induces cell surface expression of IL-13R[alpha]2. IL-13 can then signal through this high affinity receptor to increase transcription of profibrotic TGF-[beta] [7] . In cyclical fashion, TGF-[beta] is then able to further stimulate IL-13 expression [8] . However, blockade of the IL-13R[alpha]2 signaling pathway in a mouse model of inflammatory bowel disease reduced colonic levels of insulin-like growth factor-I and collagen deposition [9] . Furthermore, IL-13 slows the breakdown of collagen by downregulating matrix metalloproteinase (MMP)-2 and TNF-[alpha]-induced MMP-1 and MMP-9 synthesis [2] .

There are many sources of cytokines in inflammatory bowel disease and one which has only recently been considered is innate lymphoid cells (ILC). ILC are a recently described population of cells...

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Gale Document Number: GALE|A341859525