title: Differences in the shedding of soluble TNF receptors between endotoxin-sensitive and endotoxin-resistant mice in response to lipopolysaccharide or live bacterial challenge.
abstract: TNF-alpha plays a pivotal role in the pathogenesis of septic shock. It exerts its effects by binding two cell surface receptors, designated TNF-R I and II, also referred to as the p55 and p75 receptors, respectively. TNF-Rs are transmembrane proteins, which on cleavage of their extracellular domains, result in the release of soluble fragments (sTNF-R). sTNF-R levels increase markedly during infection, and may serve to modulate TNF-alpha bioactivity. The mechanisms regulating this process are uncertain. To investigate this, we measured sTNF-R release in endotoxin-sensitive C3H/HeN and endotoxin-resistant C3H/HeJ mice given LPS or live Gram-negative bacteria. In C3H/HeN mice, there was a rapid early response during the first 4 h, and a second peak at 8 h, particularly noticeable in the case of the p75 receptor. Prior administration of neutralizing Abs to TNF-alpha or IFN-gamma had no effect on receptor shedding. Surprisingly, C3H/HeJ mice also responded to both bacterial challenge and to LPS by shedding sTNF-R; the magnitude and duration of the early response was not substantially different from C3H/HeN mice, although the second peak was absent. Peritoneal macrophages from C3H/HeN mice responded promptly (5 h) when stimulated with LPS in vitro, and by 22 h levels had increased five- to 10-fold. In contrast, cells from C3H/HeJ mice demonstrated only a very modest response at 22 h following maximal stimulation. The data suggest that there may be at least two separately regulated pathways that control sTNF-R shedding in these mice.
authors.affiliation: Department of Infectious Diseases and Bacteriology, Hammersmith Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Carpenter
authors.forename: T J
authors.initials: TJ
authors.lastname: Evans
authors.forename: W A
authors.initials: WA
authors.lastname: Buurman
authors.forename: M H
authors.initials: MH
authors.lastname: Bemelmans
authors.forename: D
authors.initials: D
authors.lastname: Moyes
authors.forename: J
authors.initials: J
authors.lastname: Cohen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001424:Bacterial Infections / Q000276:immunology*; D002478:Cells, Cultured; D006224:Cricetinae; D005260:Female; D007371:Interferon-gamma / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008809:Mice, Inbred C3H; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma