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

• Published in: The Journal of immunology (1950) Vol. 176; no. 2; pp. 721 - 725
• Main Authors: Smookler, David S, Mohammed, Fazilat F, Kassiri, Zamaneh, Duncan, Gordon S, Mak, Tak W, Khokha, Rama
• Format: Journal Article
• Language: English
• Published: Am Assoc Immnol 15.01.2006
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.176.2.721

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-α 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.