A p55 TNF receptor immunoadhesin prevents T cell-mediated intestinal injury by inhibiting matrix metalloproteinase production.
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.
Pender
S L
SL
Department of Paediatric Gastroenterology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, United Kingdom. s.pender@mds.qmw.ac.uk
Fell
J M
JM
Chamow
S M
SM
Ashkenazi
A
A
MacDonald
T T
TT
D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D046508:Culture Techniques; D005333:Fetus; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology* / Q000293:injuries*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009924:Organ Culture Techniques; D011043:Pokeweed Mitogens / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis
D015703:Antigens, CD; D007074:Immunoglobulin G; D011043:Pokeweed Mitogens; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D008666:Metalloendopeptidases