Interleukin 1 is a key driver of inflammatory bowel disease-demonstration in a murine IL-1Ra knockout model

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.

Common contributing factors to COVID-19 and inflammatory bowel disease

“…The disintegrated immunological scenario that links AGEs to IBD also characterizes the relationship between High Fat Diets (HFDs) and IBD. HFDs have been repeatedly related to IBD [ 54 , 55 ], most possibly because of the fatty acids capacity of inducing a systemic chronic low-grade inflammation [ 56 ] marked by elevated production of the pro-inflammatory cytokines interleukin (IL)-1β [ 57 , 58 ], IL-6 [ 59 ], and TNF-α [ 60 ] in the gut. The molecular basis underlying the pathological connection between HFDs and IBD appears to be the NLRP3 inflammasome [ 61 ], with saturated fatty acids promoting NLRP3 inflammasome activation [ 62 ] and unsaturated fatty acids impeding NLRP3 activity [ 62 , 63 ].…”

Titanium Dioxide Presents a Different Profile in Dextran Sodium Sulphate-Induced Experimental Colitis in Mice Lacking the IBD Risk Gene Ptpn2 in Myeloid Cells

“…On the other hand, we discovered, that this microparticle had an opposite effect on the expression of the anti-inflammatory cytokine IL-10, down-regulating this mRNA transcript in BMDMs. Both IL-1β and IL-10 are known as important regulators of intestinal inflammation and many studies demonstrate their participation in the onset and progression of IBD [ 32 , 33 , 34 , 35 ]. It is noteworthy that, conversely to what happened in vivo, the expression pattern of these cytokines is similar between genotypes in vitro.…”

Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies

“…In contrast, mice lacking the IL-1rn gene, coding for the IL-1 receptor antagonist, spontaneously developed IBD-like abnormalities including increased immune cell infiltration and secretion of pro-inflammatory cytokines, and had an increased number of goblet cells in the jejunum and ileum compared to wild-type mice. Dosh et al reasoned that this rise in goblet cell number was due to increased expression of the transcription factors, Hath1 and Kruppel-like factor 4 (KLF4) in the inflammatory process ( 174 ). The contradictory findings of goblet cell number in IL-10 and IL-1rn deficient mice demonstrate the implications and importance of studying various genetic models reflective of the pathogenesis of intestinal inflammation.…”