A p55 TNF Receptor Immunoadhesin Prevents T Cell-Mediated Intestinal Injury by Inhibiting Matrix Metalloproteinase Production

• Published in: The Journal of immunology (1950) Vol. 160; no. 8; pp. 4098 - 4103
• Main Authors: Pender, Sylvia L. F, Fell, John M. E, Chamow, Steven M, Ashkenazi, Avi, MacDonald, Thomas T
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.04.1998
• Subjects: Antigens, CD - genetics; Antigens, CD - physiology; Culture Techniques; Fetus; Humans; Immunoglobulin G - pharmacology; Intestinal Mucosa - enzymology; Intestinal Mucosa - immunology; Intestinal Mucosa - injuries; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - biosynthesis; Organ Culture Techniques; Pokeweed Mitogens - toxicity; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - physiology; Receptors, Tumor Necrosis Factor, Type I; Recombinant Fusion Proteins - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; T-Lymphocytes - immunology; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.160.8.4098

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.