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Author(s): R. Jeroen Pasterkamp [1]; Jacques J. Peschon [2]; Melanie K. Spriggs [3]; Alex L. Kolodkin (corresponding author) [1] It is becoming increasingly clear that the nervous and immune systems [...]

A metalloproteinase that cleaves precursor tumour-necrosis factor(TNF)-alpha from cells has been purified and cloned. Soluble TNF-alpha production was significantly reduced upon the inactivation of the gene in mouse cells. The enzyme, called the TNF-alpha converting enzyme, joins the family of mammalian adamalysins. The results are expected to aid in the development of therapeutically useful inhibitors of TNF-alpha release.

The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected increases in the binding of the NF-[Kappa]B and STAT3 transcription factors shortly after PH failed to occur. Binding of AP-1 after PH was decreased in TNFR-I knockout mice compared with animals with the intact receptor whereas C/EBP binding was not modified. Injection of interleukin 6 in TNFR-I-deficient animals 30 min before PH corrected the defect in DNA synthesis and restored STAT3 and AP-1 binding to normal levels but had no effect on NF-[Kappa]B binding in the regenerating liver. The results indicate that TNF, signaling through the TNFR-I, can initiate liver regeneration and acts by activating an interleukin 6-dependent pathway that involves the STAT3 transcription factor.

The death of mature T cells can occur due to two different molecular mechanisms, tumor necrosis factor (TNF) and the Fas Ligand. TNF acts as an intermediary in T-cell death that occurs by T-cell receptor induction, and blockage of TNF and the Fas ligand are necessary to stop T-cell death. Immune responses are modulated by T cell receptor-induced apoptosis and can occur due to interactions between Fas and the Fas ligand.

The structurally related cytokines LT and TNF-α can modulate many immune and inflammatory reactions (1). LT has been identified in two different molecular forms: a secreted form consisting of an [...]

Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor (TNF), are expressed after acute hemodynamic overloading and myocardial ischemia/infarction. To define the role of TNF in the setting of ischemia/infarction, we performed a series of acute coronary artery occlusions in mice lacking one or both TNF receptors. Left ventricular infarct size was assessed at 24 h after acute coronary occlusion by triphenyltetrazolium chloride (TTC) staining in wild-type (both TNF receptors present) and mice lacking either the type 1 (TNFR1), type 2 (TNFR2), or both TNF receptors (TNFR1/TNFR2). Left ventricular infarct size as assessed by TTC staining was significantly greater (P [is less than] 0.005) in the TNFR1/ TNFR2-deficient mice (77.2% [+ or -] 15.3%)when compared with either wild-type mice (46.8% [+ or -] 19.4%) or TNFR1-deficient (47.9% [+ or -] 10.6%) or TNFR2-deficient (41.6% [+ or -] 16.5%) mice. Examination of the extent of necrosis in wild-type and TNFR1/TNFR2-deficient mice by anti-myosin Ab staining demonstrated no significant difference between groups; however, the peak frequency and extent of apoptosis were accelerated in the TNFR1/TNFR2-deficient mice when compared with the wild-type mice. The increase in apoptosis in the TNFR1/TNFR2-deficient mice did not appear to be secondary to a selective up-regulation of the Fas ligand/receptor system in these mice. These data suggest that TNF signaling gives rise to one or more cytoprotective signals that prevent and/or delay the development of cardiac myocyte apoptosis after acute ischemic injury.

Members of the ADAM (A Disintegrin And Metalloproteinase) family of metalloproteinases are membrane proteins that contain both metalloproteinase and disintegrin domains (1). The first member to be characterized was identified [...]