Abstract
Interleukin 1 (IL-1) is an important mediator of inflammation and tissue damage in inflammatory bowel disease (IBD). The balance between IL-1 and IL-1Ra as a natural inhibitor plays a vital role in a variety of diseases. Here, we investigated whether changes seen during IBD are induced spontaneously in mice lacking a functional IL-1rn gene. Histological staining was performed on the jejunum and ileum of BALB/c IL-1rn+/+ and IL-1rn-/- mice to characterize crypt-villus height, villus width, and number of goblet cells per villus. Pro-inflammatory cytokines, immune cell infiltration and matrix-degrading enzymes, together with the production of intestinal enzymes and the integrity of tight and adherent junction proteins were determined using immunohistochemistry. In the small intestine of BALB/c IL-1rn-/- mice the villus heights were significantly reduced; and in the ileum this was accompanied by a decrease in villi width. There was also an increase in goblet cell number and mucin production compared to wild-type mice. IL-1α and IL-1β immunopositivity were increased, whilst IL-1R1 expression was decreased in IL-1rn-/- mice. IL-15 and TNFα were also increased in older IL-1rn-/- mice. Increased polymorphonuclear and macrophage infiltration were seen in IL-1rn-/- mice, whilst expression of matrix-degrading enzymes and digestive enzymes were unchanged, except for dipeptidyl peptidase IV which was increased in younger IL-1rn-/- mice compared to wild type mice. The expression of tight and adhesion junctions were also dramatically decreased in IL-1rn-/- mice. In conclusion, IL-1rn-/- mice developed spontaneous abnormalities which displayed features associated with IBD, demonstrating a clear role for IL-1 in IBD.
Highlights
Inflammatory bowel disease (IBD) is a chronic autoimmune disease characterised by inflammation of the gastrointestinal tract and can be divided into two main types
Increased polymorphonuclear and macrophage infiltration were seen in IL-1rn-/- mice, whilst expression of matrix-degrading enzymes and digestive enzymes were unchanged, except for dipeptidyl peptidase Dipeptidyl peptidase 4 (IV) which was increased in younger IL-1rn-/- mice compared to wild type mice
An imbalance between Interleukin 1 (IL-1) and IL1Ra has been shown in the inflamed mucosa of patients with inflammatory bowel disease (IBD) where the levels of IL-1 and IL-Ra were increased, but importantly the ratio of Interleukin 1 receptor antagonist (IL-1Ra) to IL-1 was significantly decreased compared with controls www.oncotarget.com
Summary
Inflammatory bowel disease (IBD) is a chronic autoimmune disease characterised by inflammation of the gastrointestinal tract and can be divided into two main types. The pathogenesis of IBD is not fully understood, IBD is thought to be caused by an imbalance between pro- and anti-inflammatory cytokines in local tissues which leads to inflammation and malfunction of the barriers in the intestinal tissue. During Crohn's disease, IL-1β is significantly raised and there is a positive correlation between the severity of mucosal inflammation and the levels of IL-1β [3]. It can result in apoptosis of epithelial cells causing tissue damage and barrier dysfunction. The role of IL-1Ra in disease progression has been studied in various experimental animal models of IBD [4,5,6]
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