Effects of SEL-12 presenilin on LIN-12 localization and function in Caenorhabditis elegans

Presenilins have been implicated in the development of Alzheimer's disease and in facilitating LIN-12/Notch activity. Here, we use genetic methods to explore the relationship between C. elegans LIN-12 and SEL-12 presenilin. Reducing sel-12 activity can suppress the effects of elevated lin-12 activity when LIN-12 is activated by missense mutations but not when LIN-12 is activated by removal of the extracellular and transmembrane domains. These results suggest that SEL-12 does not function downstream of activated LIN-12. An active SEL-12::GFP hybrid protein accumulates in the perinuclear region of the vulval precursor cells (VPCs) of living hermaphrodites, consistent with a localization in endoplasmic reticulum/Golgi membranes; when sel-12 activity is reduced, less LIN-12 protein accumulates in the plasma membranes of the VPCs. Together with the genetic interactions between lin-12 and sel-12, these observations suggest a role for SEL-12 in LIN-12 processing or trafficking. However, SEL-12 does not appear to be a general factor that influences membrane protein activity, since reducing sel-12 activity does not suppress or enhance hypomorphic mutations in other genes encoding membrane proteins. We discuss potential parallels for the role of SEL-12/presenilin in facilitating LIN-12/Notch activity and in amyloid precursor protein (APP) processing.     

Interleukin-12 (IL-12) enhances lysis of non-lymphoid leukemia cell lines in vitro

IL-2 augments the ability of natural killer (NK) cells to kill myeloid leukemia cells in vitro, and may have a role in the eradication of minimal residual disease (MRD) in AML patients. The ability to enhance lysis of AML cells without the toxicity of IL-2 would be a significant improvement in the use of biologics against AML. Recent interest in IL-12 suggested that this cytokine might meet these criteria. The aim of this study was to evaluate the ability of IL-12 to enhance the in vitro lysis of the non-lymphoid leukemia cell lines in a standard 51Chromium release assay. Effector cells from normal volunteers were incubated with varying concentrations of IL-12 or IL-2 for 18-20 h, then the 51Cr-labeled target cells from five different cell lines of AML origin were added for 4 h. Percent lysis was determined and plotted over four effector:target (E:T) ratios. Our results indicated that IL-12 was able to enhance lysis of all cell lines tested at > or =5 units/ml. When IL-2 was added to the culture at a low dose along with IL-12, there appeared to be a synergistic effect. Although anti-gamma interferon was able to inhibit the cytolytic potential of effectors activated by IL-12, the lysis could not be completely blocked. Thus, it appears that IL-12 has the ability to stimulate NK lysis indirectly through the induction of gamma interferon as well as an alternate mechanism not related to gamma interferon. Thus, IL-12 may have a beneficial role in the treatment of non-lymphoid leukemia.