Tissue inhibitor of metalloproteinase 3 regulates TNF-dependent systemic inflammation.
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.
Smookler
David S
DS
Ontario Cancer Institute, University Health Network, Toronto, Canada.
Mohammed
Fazilat F
FF
Kassiri
Zamaneh
Z
Duncan
Gordon S
GS
Mak
Tak W
TW
Khokha
Rama
R
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*
D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha