Attenuated apoptosis response to Fas-ligand in active ulcerative colitis.
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.
Seidelin
Jakob B
JB
Department of Medical Gastroenterology C, Herlev Hospital, University of Copenhagen, Denmark. jseidelin@dadlnet.dk
Nielsen
Ole H
OH
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D016022:Case-Control Studies; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000378:metabolism / Q000473:pathology*; D003106:Colon / Q000187:drug effects / Q000473:pathology; D053222:Fas Ligand Protein / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D019073:HT29 Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D019014:fas Receptor / Q000378:metabolism
D000998:Antiviral Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D019014:fas Receptor; D007371:Interferon-gamma