Loss of interleukin 33 expression in colonic crypts - a potential marker for disease remission in ulcerative colitis

Abstract

Interleukin 33 (IL-33) is a cytokine preferentially elevated in acute ulcerative colitis (UC), inferring a role in its pathogenesis. The role of IL-33 in intestinal inflammation is incompletely understood, with both pro-inflammatory and regulatory properties described. There are also conflicting reports on cellular sources and subcellular location of IL-33 in the colonic mucosa, justifying a closer look at IL-33 expression in well-defined clinical stages of UC. A total of 50 study participants (29 UC patients and 21 healthy controls) were included from a prospective cohort of inflammatory bowel disease patients treated to disease remission with infliximab, a tumour necrosis factor alpha (TNF) inhibitor. To our knowledge this is the first study examining mucosal IL-33 expression before and after anti-TNF therapy. In colonic mucosal biopsies we found a 3-fold increase in IL-33 gene expression comparing acute UC to healthy controls (p < 0.01). A significant reduction of IL33 between acute UC and disease remission was observed when TNF normalised in the mucosa (p = 0.02). Immunostaining revealed IL-33 in the nuclei of epithelial cells of scattered colonic crypts in acute disease, while at disease remission, IL-33 was undetectable, a novel finding suggesting that enterocyte-derived IL-33 is induced and maintained by inflammatory mediators.

Damage-associated molecular patterns in inflammatory bowel disease: From biomarkers to therapeutic targets

“…For example, investigators found a significant increase in mucosal IL-33 mRNA expression in patients with active UC compared to healthy controls. Moreover, a significant reduction in IL-33 was detected after anti-TNF therapy, thus supporting the notion that enterocyte-derived IL-33 is induced and maintained by the inflammatory milieu[ 67 ].…”

Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease

“…Furthermore, the expression of IL-33 is correlated with the inflammatory status [69]. At the disease remission stage of UC after anti-TNF treatment, IL-33 loses its expression in colonic crypts [75]. Soluble ST2 is a sensitive marker of treatment response and clinical outcome of UC [76].…”

IL-33 and the intestine: The good, the bad, and the inflammatory

“…They also found increased mRNA expression of IL-5, IL-13, IL-15, and IL-33 in patients with UC compared to control and CD, suggestive of a prominent T H 2 immune response in UC [115]. Given the increase in mRNA expression of IL-33 in UC, it is suggestive that IL-33 may play a more significant role in UC; however, this requires further investigating [115, 116]. The similarities and differences between these immunologic profiles yield valuable clues on the pathogenesis of IBD.…”

“…In a study evaluating patients with active UC and patients in remission, they found a significant increase in mucosal IL-33 mRNA expression in patients with acute UC compared to healthy patients [116], corroborating the findings of prior studies that found increased IL-33 expression in the mucosa of the large intestine in active UC [52, 117–121]. In this study, biopsies of active UC lesions were noteworthy for the selective expression of nuclear IL-33 in enterocytes of the intestinal epithelium, specifically in the crypts [116]. This was lost with normalization of mucosal tumor necrosis factor (TNF) expression, which is indicative of disease remission following treatment with infliximab, an anti-TNF immunomodulator, in addition to a significant decrease in mucosal IL-33 expression [116].…”

“…In this study, biopsies of active UC lesions were noteworthy for the selective expression of nuclear IL-33 in enterocytes of the intestinal epithelium, specifically in the crypts [116]. This was lost with normalization of mucosal tumor necrosis factor (TNF) expression, which is indicative of disease remission following treatment with infliximab, an anti-TNF immunomodulator, in addition to a significant decrease in mucosal IL-33 expression [116]. These findings suggest IL-33 expression is increased in active UC, specifically by intestinal epithelial cells, that decreases upon disease remission.…”