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Original Article |
Correspondence to: Christoph Mueller, Institute of Pathology, Div. of Immunopathology, Murtenstrasse 31, CH-3010 Bern, Switzerland. Tel:41-31-632-89-04 Fax:41-31-381-87-64 E-mail:christoph.mueller{at}pathology.unibe.ch.
In this study, we addressed the role of tumor necrosis factor (TNF)-
and lymphotoxin (LT)-
in the development of colitis and defined the cellular sources (T cells versus non-T cells) of TNF (TNF-
and LT-
) relevant to disease development. After adoptive transfer of TNF+/+ CD4+CD45RBhi splenocytes into TNF+/+ recombination activating gene (RAG)2-/- mice, the recipients develop massive inflammation of the large intestinal mucosa concurrent with massive weight loss. In contrast, clinical signs of disease are completely absent in TNF-/-RAG2-/- recipients of TNF-/- CD4+CD45RBhi T cells, although elevated numbers of interferon-
producing cells are present in the colonic mucosa. Surprisingly, upon transfer of TNF-/-CD4+CD45RBhi T cells into TNF+/+RAG2-/- recipients, colitis develops with kinetics similar to those upon transfer of TNF+/+CD4+CD45RBhi donor cells. In contrast, no clinical signs of colitis are observed in TNF-/-RAG2-/- recipients of TNF+/+CD4+CD45RBhi T cells. This protection from colitis is not a consequence of the absence of LT-
, as TNF-
-/-RAG2-/- recipients of TNF-
-/- CD4+CD45RBhi T cells are also protected from colitis induction. These results demonstrate the importance of TNF production by non-T cells of the colonic mucosa in the pathogenesis of colitis and provide direct evidence for a nonredundant role of TNF-
in this mouse model of colitis.
Key Words: inflammatory bowel disease, mucosal immunity, intestinal inflammation, proinflammatory cytokines
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