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Gastroenterology. 2004 Sep;127(3):816-25.

Transmembrane tumor necrosis factor is a potent inducer of colitis even in the absence of its secreted form.

Author information

1
Department of Pathology, University of Bern, Bern, Switzerland.

Abstract

BACKGROUND & AIMS:

Tumor necrosis factor (TNF) is cleaved proteolytically from a 26-kilodalton transmembrane precursor protein into secreted 17-kilodalton monomers. Transmembrane (tm) and secreted trimeric TNF are biologically active and may mediate distinct activities. We assessed the consequences of a complete inhibition of TNF processing on the course of colitis in recombination activating gene (RAG)2 -/- mice on transfer of CD4 CD45RB hi T cells.

METHODS:

TNF -/- mice, transgenic for a noncleavable mutant TNF gene, were used as donors of CD4 T cells, and, on a RAG2 -/- background, also as recipients. Kinetics of disease development were compared in the absence of TNF, in the absence of secreted TNF, and in the presence of secreted and tmTNF. The analysis at the end of the observation period included the histopathologic assessment of the intestine and the localization of TNF and interferon gamma (IFNgamma)-expressing cells.

RESULTS:

The complete prevention of TNF secretion in tmTNF transgenic RAG2 -/- mice neither prevented nor delayed disease induction by transferred transgenic for a noncleavable transmembrane mutant of mouse TNF (tmTNF tg) CD4 CD45RB hi T cells. tmTNF expression by transferred CD4 T cells, however, was not required for disease induction because severe colitis and weight loss also were observed in tmTNF RAG2 -/- recipients of TNF -/- CD4 CD45RB hi T cells. In the presence of tmTNF, the absence of secreted TNF did not affect frequency and distribution of TNF and interferon-gamma messenger RNA (mRNA)-expressing cells.

CONCLUSIONS:

These results indicate that specific inhibitors of TNF processing are not appropriate for modulating the pro-inflammatory and disease-inducing effects of TNF in chronic inflammatory disorders of the intestine.

PMID:
15362037
DOI:
10.1053/j.gastro.2004.06.036
[Indexed for MEDLINE]

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