CD95 is cytoprotective for intestinal epithelial cells in colitis.
BACKGROUND
CD95 is a member of the tumor necrosis factor receptor family. It is constitutively expressed on the basolateral membrane of intestinal epithelial cells (IECs) and under certain conditions induces apoptosis when crosslinked by its natural ligand, CD95L. A multitude of studies have been published addressing the question of where and under which conditions CD95L is produced in the gut in normal, inflammatory, and neoplastic situations and whether the apoptosis-inducing activity of CD95 contributes to pathology. Although some of these studies have considerably influenced our view on the role of the CD95/CD95L system compelling evidence for an involvement of the CD95/CD95L system in the physiological epithelial cell turnover is lacking.


METHODS
CD95 signaling deficiency in the colon was achieved in 2 ways. By transplanting bone marrow from wildtype mice into lethally irradiated mice expressing a signaling deficient mutant of CD95 (lpr(cg) mice) and by tissue-specific deletion of CD95 in IECs. Mice were treated with either 3 cycles of dextran sulfate sodium (DSS) to induce colitis or by injection of azoxymethane (AOM) followed by 3 cycles of DSS to induce colon cancer. Disease index and the formation of neoplastic lesions in the colon were determined and histological analysis was performed.


RESULTS
In each mouse model lacking CD95 activity in the colon mice were hypersensitive to DSS-induced colitis. In the CD95-deficient mice this did not have an effect on AOM/DSS-induced cancer formation.


CONCLUSIONS
CD95 plays a role in protecting the colon from inflammation without contributing to colon cancer, under conclusions of increased inflammation.
Park
Sun-Mi
SM
Ben May Department for Cancer Research, Johns Hopkins Medical Institute, Baltimore, Maryland, USA.
Chen
Lina
L
Zhang
Manling
M
Ashton-Rickardt
Philip
P
Turner
Jerrold R
JR
Peter
Marcus E
ME
D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
D002273:Carcinogens; D053222:Fas Ligand Protein; D019014:fas Receptor; D016264:Dextran Sulfate; D001397:Azoxymethane