| First Author | Smookler DS | Year | 2006 |
| Journal | J Immunol | Volume | 176 |
| Issue | 2 | Pages | 721-5 |
| PubMed ID | 16393953 | Mgi Jnum | J:126607 |
| Mgi Id | MGI:3761738 | Doi | 10.4049/jimmunol.176.2.721 |
| Citation | Smookler DS, et al. (2006) Tissue inhibitor of metalloproteinase 3 regulates TNF-dependent systemic inflammation. J Immunol 176(2):721-5 |
| abstractText | 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. |
