CD44v7 ligation downregulates the inflammatory immune response in Crohn's disease patients by apoptosis induction in mononuclear cells from the lamina propria.
Deletion of exon CD44v7 abrogates experimental colitis by apoptosis induction in intestinal mononuclear cells. Here we show that CD44v7 expression was upregulated upon CD40 ligation in human mononuclear cells, and examined whether ligation of CD44v7 also affects activation and apoptosis in lamina propria mononuclear cells (LPMC) from Crohn's disease (CD) patients. Thirty five patients with chronic inflammatory bowel disease (IBD), fourteen controls and four patients with diverticulitis were evaluated. CD44v7 was upregulated predominantly in the inflamed mucosa of CD patients. Furthermore, incubation with an anti-CD44v7 antibody induced apoptosis in LPMC isolated from inflamed mucosa of CD patients, but not from non-inflamed mucosa, from patients with ulcerative colitis (UC) or from normal controls. CD40 ligation and simultaneous incubation with anti-CD44v7 significantly downregulated CD80 in dendritic cells, thus inhibiting a critical second signal for naive T-cell activation. The apoptotic signal was mediated via the intrinsic mitochondrial pathway with decreased Bcl-2 and increased 7A6 (a mitochondrial membrane protein) expression. It was Fas independent and required caspases-3 and -9 activation. The process is highly specific for macrophage activation via CD40. These findings point to a novel mechanism of apoptosis induction in CD patients mediated by CD44v7 ligation.
Hoffmann
U
U
Medical Clinic 1, Department for Gastroenterology, Infectiology and Rheumatology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin D 12200, Germany.
Heilmann
K
K
Hayford
C
C
Stallmach
A
A
Wahnschaffe
U
U
Zeitz
M
M
Günthert
U
U
Wittig
B M
BM
D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008875:Middle Aged; D008928:Mitochondria / Q000276:immunology; D009092:Mucous Membrane / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation
D019013:CD40 Antigens; C497483:CD44 protein, human; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors