Phorbol Ester-induced Shedding of the Prostate Cancer Marker Transmembrane Protein with Epidermal Growth Factor and Two Follistatin Motifs 2 Is Mediated by the Disintegrin and Metalloproteinase-17

The transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is expressed in prostate and brain and shed from the cell surface in a metalloproteinase-dependent fashion. Neither the sheddase(s) responsible for TMEFF2 shedding nor the physiological significance or activity of the soluble TMEFF2 ectodomain (TMEFF2-ECD) has been identified. In the present study we present new evidence that a disintegrin and metalloproteinase-17 (ADAM17) is responsible for phorbol 12-myristate 13-acetate-induced release of TMEFF2-ECD using small interfering RNA to ablate ADAM17 expression or by inhibiting enzymatic activity. A single well shedding assay monitoring the release of alkaline phosphatase-tagged TMEFF2-ECD into medium and the generation of 22- and 14-kDa C-terminal fragments in lysates were dependent on ADAM17 activity. A γ-secretase inhibitor prevented the formation of a 10-kDa fragment in cell lysates, thus establishing TMEFF2 as a novel substrate for regulated intramembrane proteolysis. We assigned proliferation-inducing activity to TMEFF2. Inhibition of TMEFF2 shedding using synthetic metalloproteinase inhibitors or small interfering RNA targeting TMEFF2 expression yielded a statistically significant reduction of cell proliferation in the lymph node-derived prostate cancer cells (LNCaPs) and a human embryonic kidney (HEK293) cell line overexpressing TMEFF2. The TMEFF2-ECD was able to induce ERK1/2 phosphorylation in an epidermal growth factor receptor (or ErbB1)-dependent manner in HEK293 cells. Our data suggest that TMEFF2 contributes to cell proliferation in an ADAM17-dependent autocrine fashion in cells expressing this protein

Acute inflammation and psychomotor slowing: Experimental assessment using lipopolysaccharide administration in healthy humans

Data from clinical and cross-sectional studies suggest that inflammation contributes to psychomotor slowing and attentional deficits found in depressive disorder. However, experimental evidence is still lacking. The aim of this study was to clarify the effect of inflammation on psychomotor slowing using an experimental and acute model of inflammation, in which twenty-two healthy volunteers received an intravenous injection of lipopolysaccharide (LPS, dose: 0.8 ​ng/kg body weight) and of placebo, in a randomized order following a double-blind within-subject crossover design. A reaction time test and a go/no-go test were conducted 3 ​h after the LPS/placebo injection and interleukin (IL)-6 and tumor necrosis factor (TNF)-α concentrations were assessed. No effect of experimental inflammation on reaction times or errors for either test was found. However, inflammation was related to worse self-rated performance and lower effort put in the tasks. Exploratory analyses indicated that reaction time fluctuated more over time during acute inflammation. These data indicate that acute inflammation has only modest effects on psychomotor speed and attention in healthy subjects objectively, but alters the subjective evaluation of test performance. Increased variability in reaction time might be the first objective sign of altered psychomotor ability and would merit further investigation