Enhanced susceptibility to Con A-induced liver injury in mice transgenic for the intracellular isoform of human TNF receptor type 2.
TNF is a pleiotropic cytokine involved in a variety of inflammatory processes and immune responses. TNF effects are mediated via two distinct membrane receptors: TNFR1 and TNFR2. Investigations concerning regulation and function of TNFR2 revealed a novel TNFR2 isoform in human and mouse cells, termed icp75TNFR, with mainly intracellular localization. As human icp75TNFR is capable of functional interaction with mouse TNF, mouse lines transgenic for the human icp75TNFR were generated and characterized. Transgenic expression was identified in several organs, and soluble human (sh)TNFR2 was detected in serum. shTNFR2 released from transfected cells or peritoneal macrophages of transgenic mice protected from TNF-induced cytotoxicity. Although in vivo, no change in inflammatory reactions was observed in models of septic peritonitis, of colitis, or after stimulation with bacterial LPS, liver injury was strongly enhanced in transgenic mice after Con A challenge. Thus, the functional properties of human icp75TNFR seem to be similar to that of TNFR2, resulting in exacerbation of inflammatory tissue damage, thus revealing the functional importance of TNFR2 in pathophysiological processes.
Bäumel
Monika
M
Department of Immunology, University of Regensburg, F.-J.-Strauss-Allee, D-93042 Regensburg, Germany.
Lechner
Anja
A
Hehlgans
Thomas
T
Männel
Daniela N
DN
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury; D003208:Concanavalin A; D004198:Disease Susceptibility; D005688:Galactosamine / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008107:Liver Diseases / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009500:Neutralization Tests; D020033:Protein Isoforms / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D012995:Solubility / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D020033:Protein Isoforms; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D005688:Galactosamine