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  • Title: Interactions between octaarginine and U-937 human macrophages: global gene expression profiling, superoxide anion content, and cytokine production.
    Author: Kuo JH, Jan MS, Lin YL, Lin C.
    Journal: J Control Release; 2009 Nov 03; 139(3):197-204. PubMed ID: 19619591.
    Abstract:
    Cell penetrating peptides such as octaarginine (R8) have been widely used as intracellular delivery vectors to import biologically active membrane-impermeable molecules. However, before using these peptides clinically, human immune responses to them must be fully understood. Because macrophages are important for immune responses, we evaluated the interactions between R8 and a human U-937 cell line. Cytotoxicity, binding, internalization, genome-wide profiling of gene expression, intracellular superoxide anion content, and cytokine release were assessed after U-937 cells had been incubated with different amounts of R8. Cytotoxicity was limited for up to 40 microM of R8 and 24 h of incubation. Kinetic analysis of the binding and uptake of cells treated with fluorescein-5-isothiocynate-R8 showed time- and concentration-dependent increases. Microarray analysis identified 4386 genes time-dependently regulated when U-937 macrophages were exposed to 10 microM of R8 for 0.5 h and 4 h; the majority of these genes were upregulated for each time point. Thirty-five upregulated genes responded to the stimuli with immune functions, and, using real-time quantitative reverse transcriptase-polymerase chain reaction analysis, five genes - FOS, OSM, C1R, TNF, IL1R1 - were confirmed. R8 induced superoxide anion production after 0.5 h, but not after longer incubations. Incubating U-937 cells with R8 for up to 24 h did not release the proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6. In summary, exposing U-937 macrophages to R8 did not induce proinflammatory cytokine release; however, it generated superoxide anion and affected gene expression.
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