Recombinant human granulocyte colony-stimulating factor (rhG-CSF) induced migration across polycarbonate filters of human polymorphonuclear leukocytes (PMN). rhG-CSF was active in inducing PMN migration at concentrations greater than or equal to 10 to 100 U/mL (7 to 70 ng/mL). rhG-CSF did not contain appreciable levels of endotoxin contamination as assessed by Limulus amebocyte assay, and Polymixin B did not affect the chemotactic activity of rhG-CSF. A monoclonal anti-G- CSF antibody blocked the induction of migration by G-CSF, thus establishing that the cytokine was responsible for the activity of the recombinant preparation. Checkerboard analysis was performed by seeding different concentrations of G-CSF above and/or below the filter and revealed that the migratory response to this cytokine was best observed in the presence of a positive concentration gradient between the lower and upper compartments of the chamber, thus indicating an actual chemotactic effect. When different migrating cells were examined, rhG- CSF was inactive on large granular lymphocytes and endothelial cells under conditions in which appropriate reference attractants were active. In contrast, rhG-CSF elicited a chemotactic response in monocytes inhibited by specific antibody. Thus, G-CSF is a chemotactic signal for phagocytes. This cytokine, when produced at inflammatory sites, may contribute to the recruitment of phagocytes from the blood compartment to amplify resistance against certain noxious agents.

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The IjB kinase (IKK)/NF-jB pathway has been shown to be a major regulator in cell survival. However, the mechanisms through which IKK mediates cell death are not clear. In this study, we showed that IKK-b contributed to hydrogen peroxide (H 2 O 2 )-induced cell death independent of the NF-jB pathway. Our results demonstrated that the pro-death function of IKK-b under oxidative stress was mediated by p85 S6K1 (S6 kinase 1), but not p70 S6K1 through a rapamycin-insensitive and mammalian target of rapamycin complex 1 kinase-independent mechanism. We found that IKK-b associated with p85, but not p70 S6K1, which was required for H 2 O 2 -induced activation of p85 S6K1. IKK-b and p85 S6K1 contributed to H 2 O 2 -induced phosphorylation of Mdm2 (S166) and p53 accumulation. p85 S6K1 is critical for IKK-b-mediated cell death. Thus, these findings established a novel oxidative stress-responsive pathway that involves IKK-b, p85 S6K1 and Mdm2, which is response for H 2 O 2 -induced cell death. Our results have important implications for IKK-b and p85 S6K1 as potential targets for the prevention of diseases involved in oxidative stress-induced aberrant cell death. Reactive oxygen species (ROS), such as hydrogen peroxide (H 2 O 2 ), are generated in cells as a consequence of oxidative metabolism. Although low levels of ROS are usually detoxified quickly by antioxidant enzymes, an excessive accumulation of ROS may result in oxidative stress. High and/or persistent levels of oxidative stress represent a major cause of cellular damage and aberrant death in a plethora of pathological conditions during the initiation and progression of a plethora of pathological conditions, including neurodegenerative diseases, cancer, autoimmune and the ageing process.1 While ROS may trigger cell death through multiple mechanisms, 2 recent studies have established the nuclear factor-kB (NF-kB) pathway as a critical signaling pathway in mediating the action of ROS in cell survival/cell death.

Increased average diffusion coefficient in adult brains with aging are consistent with findings regarding structural changes in the brain that have been associated with aging. The study also demonstrates that it is desirable to use the same experimental parameters for diffusion coefficient quantification when comparing between different subjects and groups of interest.

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