TY - JOUR

T1 - Attenuated apoptosis response to Fas-ligand in active ulcerative colitis

AU - Seidelin, Jakob B

AU - Nielsen, Ole H

PY - 2008/12

Y1 - 2008/12

N2 - BACKGROUND: From mainly carcinoma cell line studies, apoptosis has been thought to play a major role in the pathogenesis of ulcerative colitis (UC). Apoptosis has been suggested to be due to a Fas ligand / Fas receptor interaction, but has never been studied in cells from patients with active UC. The aim was to investigate both the spontaneous and the cell death receptor ligand-induced apoptosis in UC.METHODS: Twenty patients with UC and 16 control subjects who underwent routine colonoscopy either for the control or surveillance of their disease or where the diagnosis of irritable bowel syndrome was subsequently reached were included. Cultures of isolated colonic crypts were obtained from biopsies and cultured for 4 to 16 hours with Fas ligand or Fas ligand and costimulation with interferon-gamma (IFN-gamma). Control experiments were performed on HT29 cells. Apoptosis was assessed by independent methods.RESULTS: Isolated colonocytes from healthy subjects or patients with remission in UC had a dose-dependent response to Fas ligand. This response was abolished in patients with active UC (P < 0.002), and costimulation with IFN-gamma did not alter this response. Patients with active UC had an increased apoptosis rate of 9.5% compared with controls (P < 0.05).CONCLUSIONS: The current study indicates that colonocytes do not respond to cytokine exposure and inflammation by an increased vulnerability, as previously thought. Colonocytes seem to activate cytoprotective programs in response to inflammation. Apart from supporting the regeneration process during inflammation, this response could additionally cause an increased susceptibility to neoplastic transformation.

AB - BACKGROUND: From mainly carcinoma cell line studies, apoptosis has been thought to play a major role in the pathogenesis of ulcerative colitis (UC). Apoptosis has been suggested to be due to a Fas ligand / Fas receptor interaction, but has never been studied in cells from patients with active UC. The aim was to investigate both the spontaneous and the cell death receptor ligand-induced apoptosis in UC.METHODS: Twenty patients with UC and 16 control subjects who underwent routine colonoscopy either for the control or surveillance of their disease or where the diagnosis of irritable bowel syndrome was subsequently reached were included. Cultures of isolated colonic crypts were obtained from biopsies and cultured for 4 to 16 hours with Fas ligand or Fas ligand and costimulation with interferon-gamma (IFN-gamma). Control experiments were performed on HT29 cells. Apoptosis was assessed by independent methods.RESULTS: Isolated colonocytes from healthy subjects or patients with remission in UC had a dose-dependent response to Fas ligand. This response was abolished in patients with active UC (P < 0.002), and costimulation with IFN-gamma did not alter this response. Patients with active UC had an increased apoptosis rate of 9.5% compared with controls (P < 0.05).CONCLUSIONS: The current study indicates that colonocytes do not respond to cytokine exposure and inflammation by an increased vulnerability, as previously thought. Colonocytes seem to activate cytoprotective programs in response to inflammation. Apart from supporting the regeneration process during inflammation, this response could additionally cause an increased susceptibility to neoplastic transformation.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antigens, CD95

KW - Antiviral Agents

KW - Apoptosis

KW - Case-Control Studies

KW - Cells, Cultured

KW - Colitis, Ulcerative

KW - Colon

KW - Fas Ligand Protein

KW - Female

KW - Flow Cytometry

KW - Fluorescent Antibody Technique

KW - HT29 Cells

KW - Humans

KW - Interferon-gamma

KW - Male

KW - Middle Aged

KW - Young Adult

KW - Comparative Study

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/ibd.20629

DO - 10.1002/ibd.20629

M3 - Journal article

C2 - 18680199

VL - 14

SP - 1623

EP - 1629

JO - Inflammatory Bowel Diseases

JF - Inflammatory Bowel Diseases

SN - 1078-0998

IS - 12

ER -