title: Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine Family, in Inflammatory Bowel Disease.
abstract: BACKGROUND
  Interleukin (IL)-36 (IL-36α, IL-36β, and IL-36γ) is a recently reported member of the IL-1 cytokine family. In this study, we investigated IL-36 expression in the inflamed mucosa of patients with inflammatory bowel disease and characterized the proinflammatory actions of IL-36 cytokines in human colonic epithelial cells.
  
  
  METHODS
  IL-36 mRNA expression was evaluated using real-time PCR. IL-36 protein expression was analyzed using immunoblotting and immunohistochemical technique. Intracellular signaling pathways were evaluated by immunoblotting and by specific siRNA-transfected cells.
  
  
  RESULTS
  The mRNA expression of IL-36α and IL-36γ, but not of IL-36β, was enhanced in the inflamed mucosa of patients with inflammatory bowel disease, in particular, in ulcerative colitis. Immunohistochemical analysis showed that T cells, monocytes, and plasma cells are the source of IL-36α and IL-36γ in colonic mucosa. DNA microarray analysis indicated that IL-36α induces the mRNA expression of CXC chemokines and acute phase proteins in intestinal epithelial cell line, HT-29 cells. IL-36α and IL-36γ dose-dependently and time-dependently induced the mRNA and protein expression of CXC chemokines (CXCL1, CXCL2, CXCL3 etc.) in HT-29 and Widr cells. Stimulation with IL-36α and IL-36γ assembled MyD88 adaptor proteins (MyD88, TRAF6, IRAK1, and TAK1) into a complex and induced the activation of NF-κB and AP-1 and also the phosphorylation of MAPKs. MAPK inhibitors and siRNAs specific for NF-κB and c-Jun AP-1 significantly reduced IL-36-induced CXC chemokine expression.
  
  
  CONCLUSIONS
  IL-36α and IL-36γ may play a proinflammatory role in the pathophysiology of inflammatory bowel disease through induction of CXC chemokines and acute phase proteins.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nishida
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hidaka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kanda
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Imaeda
authors.forename: Makoto
authors.initials: M
authors.lastname: Shioya
authors.forename: Osamu
authors.initials: O
authors.lastname: Inatomi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Bamba
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kitoh
authors.forename: Mitsushige
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Akira
authors.initials: A
authors.lastname: Andoh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002478:Cells, Cultured; D005500:Follow-Up Studies; D019073:HT29 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D007375:Interleukin-1; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C572887:interleukin 36, human