IL-33 is upregulated in colonocytes of ulcerative colitis.
Interleukin-33 (IL-33) is a novel member of the IL-1 cytokine family. It has been shown to elicit a Th2-like cytokine response in immunocompetent cells through binding and activation of the T1/ST2 receptor. IL-33 has recently been associated with immune responses to helminthic intestinal infections, airway inflammation and arthritis in animal models. We now report IL-33 to be produced by colonic epithelial cells in humans and it is highly upregulated in ulcerative colitis (UC). Little mRNA expression was found in control subjects (N=9), whereas patients with UC in remission (N=7) and active UC (N=9) had a 3-fold (p<0.006) and 13-fold (p<0.0002) increased expression, respectively. On the protein level, IL-33 in its uncleaved form was overexpressed in active UC compared to controls (p<0.006) and inactive UC (p<0.03). Immunohistochemistry of IL-33 confirmed expression in active UC in colonic epithelial cells, whereas no detectable epithelial expression was seen in control specimens. Caspase 1, which is known to activate IL-33, was expressed in colonocytes, albeit at just detectable levels when the activated p20 caspase 1 was measured. Since IL-33 recently has been shown to be biologically active in its pro-form, and cleavage seems to inactivate IL-33, IL-33 is suggested to be active in UC. We found no IL-33 expression in Caco2 cells, regardless of stimulation by pro-inflammatory cytokines. In contrast to the IL-33 expression data, we could not show any difference in the production of another member of the IL-1 cytokine family, IL-1beta. This is the first study to describe that IL-33 is upregulated in UC. If IL-33 is driving a Th2-like cytokine response in UC, inhibition of the IL-33 T1/ST2 receptor pathway could be a future therapeutic option in UC.
Seidelin
Jakob Benedict
JB
Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Denmark. jseidelin@dadlnet.dk
Bjerrum
Jacob Tveiten
JT
Coskun
Mehmet
M
Widjaya
Budiman
B
Vainer
Ben
B
Nielsen
Ole Haagen
OH
D000328:Adult; D000368:Aged; D018938:Caco-2 Cells; D020170:Caspase 1 / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000473:pathology; D018450:Disease Progression; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015854:Up-Regulation
C506536:IL33 protein, human; D053583:Interleukin-1beta; D000067596:Interleukin-33; D007378:Interleukins; D020170:Caspase 1