A p55 TNF receptor immunoadhesin prevents T cell-mediated intestinal injury by inhibiting matrix metalloproteinase production
| Autor: | S L, Pender, J M, Fell, S M, Chamow, A, Ashkenazi, T T, MacDonald |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Tissue Inhibitor of Metalloproteinase-1
Recombinant Fusion Proteins T-Lymphocytes Metalloendopeptidases Receptors Tumor Necrosis Factor Fetus Organ Culture Techniques Pokeweed Mitogens Antigens CD Receptors Tumor Necrosis Factor Type I Culture Techniques Immunoglobulin G Humans RNA Messenger Intestinal Mucosa |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 160(8) |
| ISSN: | 0022-1767 |
| Popis: | Anti-TNF-alpha Ab therapy has been shown to be of benefit in the treatment of active Crohn's disease, but the tissue-injuring processes in the gut mediated by TNF-alpha that might be inhibited by neutralizing Ab are unknown. In this work, we have used a p55 TNF receptor-human IgG fusion protein (TNFR-IgG) to prevent the severe mucosal injury that ensues when lamina propria T cells in explant cultures of human fetal small intestine are directly activated with the lectin PWM. Following T cell activation and associated with mucosal injury, there is a marked elevation of soluble TNF-alpha in organ culture supernatants and a large increase in TNF-alpha mRNA transcripts. The addition of TNFR-IgG at the onset of cultures greatly reduced PWM-induced tissue injury, without inhibiting the increase in TNF-alpha and IFN-gamma transcripts seen following T cell activation. Mucosal injury in this model is mediated by endogenously-produced matrix metalloproteinases (MMPs). When TNFR-IgG was added to PWM-stimulated explants, there was a reduction in MMPs in the explant culture supernatants, especially stromelysin-1. Recombinant TNF-alpha and IL-1beta added directly to mucosal mesenchymal cell lines also caused an increase in MMP production, but only the former was inhibited by the TNFR-IgG. These results suggest that one of the ways in which TNF-alpha causes tissue injury in the gut is by stimulating mucosal mesenchymal cell to secrete matrix-degrading metalloproteinases. Neutralization of this activity should help maintain tissue integrity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|