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Cutting Edge: Tissue Inhibitor of Metalloproteinase 3 Regulates TNF-Dependent Systemic Inflammation

Ontario Cancer Institute, University Health Network, Toronto, Canada

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- 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.

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