Tumor necrosis factor-receptor 2 is up-regulated on lamina propria T cells in Crohn's disease and promotes experimental colitis in vivo.
Tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of Crohn's disease (CD). However, little is known about the role of TNF receptors (TNF-R) in this disease. Here, we found that TNF-R2 (in contrast to TNF-R1) was significantly up-regulated on lamina propria and peripheral blood T cells in CD compared to control patients. To directly test the functional role of TNF-R2 in Th1-mediated experimental colitis in vivo, we took advantage of transgenic animals overexpressing TNF-R2 in T cells. Reconstitution of SCID mice with CD4+ CD62L+ T cells from TNF-R2 transgenic mice led to an earlier wasting syndrome, a more severe colitis and augmented Th1 cytokine production than reconstitution with cells from wild-type littermates. In addition, TUNEL staining revealed a significantly decreased apoptosis rate of lamina propria mononuclear cells in mice reconstituted with TNF-R2 transgenic T cells compared to mice reconstituted with wild-type T cells. In summary, our data suggest a critical regulatory role of TNF-R2 signaling for disease exacerbation in Th1-mediated chronic colitis. Taken together with the increased expression of TNF-R2 in CD, selective targeting of TNF-R2 signaling thus emerges as a potentially novel approach to the treatment of CD.
Holtmann
Martin H
MH
Laboratory of Immunology, I. Medical Clinic, University of Mainz, Mainz, Germany.
Douni
Eleni
E
Schütz
Michael
M
Zeller
Geraldine
G
Mudter
Jonas
J
Lehr
Hans-Anton
HA
Gerspach
Jeanette
J
Scheurich
Peter
P
Galle
Peter R
PR
Kollias
George
G
Neurath
Markus F
MF
D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology*; D017209:Apoptosis; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology*; D003106:Colon / Q000276:immunology*; D003424:Crohn Disease / Q000209:etiology / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013601:T-Lymphocytes / Q000378:metabolism*; D015854:Up-Regulation
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015847:Interleukin-4; D007371:Interferon-gamma