OX40/OX40L interaction induces the expression of CXCR5 and contributes to chronic colitis induced by dextran sulfate sodium in mice.
Interactions between APC and T lymphocytes have been implicated as a major factor contributing to inflammatory bowel disease. To test whether OX40/OX40L interaction plays a role in chronic intestinal inflammation, we induced chronic colitis using dextran sulfate sodium and treated the mice with a murine fusion protein (OX40-IgG). Treatment resulted in a dose-dependent and significant reduction of intestinal inflammation (46%) as measured by a histologic score. IL-10 and IL-5 production from mesenteric lymph node cells increased 20-fold and 18-fold, respectively. In colonic tissue, IL-10 mRNA levels increased and the expression of T-bet was decreased to 30%. IL-10 neutralization partly inhibited the beneficial effects of OX40-IgG treatment. Surprisingly, despite the reduction of inflammation we found the number and size of colonic lymphoid follicles increased, with an accumulation of CD4(+) cells in the mantle area. In contrast, the number of CD4(+) cells infiltrating the mucosa was significantly reduced, as was their CXCR5 expression (24-fold). We conclude that OX40/OX40L interaction contributes to the perpetuation of chronic colitis partly by suppressing IL-10 production. Furthermore, our data suggest that the OX40/OX40L-induced CXCR5 expression on CD4(+) cells may be important for the inflammatory process by allowing migration to the germinal center for further differentiation of CD4(+) cells before they infiltrate the chronically inflamed mucosa.
Obermeier
Florian
F
Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. Florian.Obermeier@klinik.uni-regensberg.de
Schwarz
Herbert
H
Dunger
Nadja
N
Strauch
Ulrike G
UG
Grunwald
Nicole
N
Schölmerich
Jürgen
J
Falk
Werner
W
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002908:Chronic Disease; D003092:Colitis / Q000209:etiology*; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000633:toxicity*; D005260:Female; D016753:Interleukin-10 / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053278:OX40 Ligand; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000502:physiology*; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology*; D048069:Tumor Necrosis Factors
C513179:CXCR5 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors; D016753:Interleukin-10; D016264:Dextran Sulfate