title: Differences in goblet cell differentiation between Crohn's disease and ulcerative colitis.
abstract: Goblet cells are mucin-secreting intestinal cells forming the mucus layer that protects the mucosal surface. Ulcerative colitis (UC) has been associated with a defective colonic mucus layer and a reduced number of goblet cells. In experimental animals, colonic goblet cell differentiation is regulated by interacting transcription factors Hath1, KLF4 and the Notch, as well as Wnt pathways, whereas data in humans are limited. We investigated goblet cell differentiation factors and mucins in controls and in inflammatory bowel diseases (IBDs). We performed real-time PCR for Hath1, KLF4, several ligands, receptors and target genes of the Notch and Wnt pathways, as well as several mucins in biopsies from the sigmoid colon of controls (n=21), Crohn's disease (CD, n=48) and UC (n=40). In addition, Hath1 protein was quantitated with Western blot and localized with immunohistochemistry. Notably, the degree of inflammation as measured by IL-8 and histology was similar in both disease entities. The proportion of goblet cells was lowered in both IBDs, but specifically diminished in the upper third of the crypt in UC. Comparable levels of inflammation induced both Hath1 (2.0-fold, p<0.001) and KLF4 (1.8-fold for KLF4, p=0.031) mRNA expression in CD but not in UC (0.8-0.9-fold, ns). The differential induction was confirmed for Hath1 protein using Western blot. Hath1 immunostaining was found mostly in the lower half of the colonic crypts. Hath1, KLF4 and the Notch target gene Hes1 were significantly (p<0.001) and positively correlated. Moreover, both Hath1 and KLF4 were correlated (p<0.001) with MUC1, MUC2 as well as MUC4 in all control and IBD cohorts. The results indicate that both transcription factors are key regulators of goblet cell differentiation and mucin formation in the human colon. Conspicuously, inflammation is associated with an enhanced goblet cell differentiation in CD but not in UC, a defect possibly of pathogenic importance.
authors.affiliation: Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gersemann
authors.forename: Svetlana
authors.initials: S
authors.lastname: Becker
authors.forename: Irmgard
authors.initials: I
authors.lastname: Kübler
authors.forename: Maureen
authors.initials: M
authors.lastname: Koslowski
authors.forename: Guoxing
authors.initials: G
authors.lastname: Wang
authors.forename: Klaus Robert
authors.initials: KR
authors.lastname: Herrlinger
authors.forename: Joscha
authors.initials: J
authors.lastname: Griger
authors.forename: Peter
authors.initials: P
authors.lastname: Fritz
authors.forename: Klaus
authors.initials: K
authors.lastname: Fellermann
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Jan
authors.initials: J
authors.lastname: Wehkamp
authors.forename: Eduard Friedrich
authors.initials: EF
authors.lastname: Stange
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001706:Biopsy; D002454:Cell Differentiation; D003093:Colitis, Ulcerative / Q000473:pathology*; D012809:Colon, Sigmoid / Q000473:pathology*; D003113:Colonoscopy; D003424:Crohn Disease / Q000473:pathology*; D020397:Goblet Cells / Q000166:cytology*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D009077:Mucins / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009077:Mucins; D051880:Receptors, Notch; D051153:Wnt Proteins; C500942:ATOH1 protein, human; C000715467:KLF4 protein, human