title: Tissue inhibitor of metalloproteinase 3 regulates TNF-dependent systemic inflammation.
abstract: Host response to infectious agents must be rapid and powerful. One mechanism is the release of presynthesized membrane-bound TNF. TNF shedding is mediated by TNF-alpha converting enzyme, which is selectively inhibited by the tissue inhibitor of metalloproteinase 3 (TIMP3). We show that loss of TIMP3 impacts innate immunity by dysregulating cleavage of TNF and its receptors. Cultured timp3-/- macrophages release more TNF in response to LPS than wild-type macrophages. In timp3-/- mice, LPS causes serum levels of TNF and its receptors to rise more rapidly and remain higher compared with wild-type mice. The altered kinetics of ligand and receptor shedding enhances TNF signaling in timp3-/- mice, indicated by elevated serum IL-6. Physiologically, timp3-/- mice are more susceptible to LPS-induced mortality. Ablation of the TNF receptor gene p55 (Tnfrsf1a) or treatment with a synthetic metalloproteinase inhibitor rescues timp3-/- mice. Thus, TIMP3 is essential for normal innate immune function.
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Smookler
authors.forename: Fazilat F
authors.initials: FF
authors.lastname: Mohammed
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Duncan
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha