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U 937 cells are widely used as a model system to study human monocytes, since they express typical human monocyte markers and properties. Hexadecylphosphocholine (HPC) is the main representative of a class of synthetic phospholipids, the alkylphosphocholines (APCs), and is able to form stable multilamellar vesicles (MLVs = liposomes) to deliver HPC to monocytes/macrophages. Here we report the ability of both micellar and liposomal HPC (L-HPC) to interact with human monocytes and upregulate specific adhesion molecules. Whereas CD14 could neither be induced by HPC nor by L-HPC on U 937 cells, intracellular adhesion molecule-1 and class 1 major histocompatibility complex (MHC-1) antigen were upregulated by both HPC and L-HPC in a dose-dependent manner. These data support and complete previous studies on HPC-induced activation of U 937 cells and provide additional mechanistic information on the initial steps of HPC-mediated recruitment of macrophages and their antitumor activity.

The myeloid-related proteins MRP8 (S100A8) and MRP14 (S100A9), two members of the S100 family of calcium-binding proteins, are co-expressed and form a cell-surface and cytoskeleton-associated heterodimer upon calcium mobilization which is recognized by the mAb 27E10. The heterodimer is abundantly expressed in the cytoplasm of granulocytes and a subpopulation of blood monocytes. Previously, we and others demonstrated endothelium-associated MRP8/14 in inflamed tissues in the vicinity of transmigrating leukocytes, suggesting a function of the proteins in this process. Here, we demonstrate that 27E10(+) cells represent a fast-migrating monocyte subpopulation which preferentially utilizes an ICAM-1-dependent mechanism. The following observations imply a function of MRP8/14 in the transmigration process: (i) higher secretion of MRP8/14 from 27E10(+) monocytes compared to 27E10(-) monocytes after interaction with activated endothelium, (ii) higher expression of CD11b on 27E10(+) compared to 27E10(-) monocytes, (iii) up-regulation of CD11b on 27E10(-) monocytes in the presence of MRP14 or MRP8/14 heterodimers but not MRP8 and (iv) active participation of MRP14 but not of MRP8 in transmigration as shown by blocking with respective antibodies. We show that the interaction of 27E10(+) monocytes with activated endothelium leads to MRP8/14 release which may account for the high MRP8/14 concentrations in body fluids of patients with acute or chronic inflammatory diseases. Released MRP8/14 may serve a function by enhancing CD11b expression and/or affinity in human monocytes and by participating in the transendothelial migration mechanism. Thus, MRP8/14 substantially contributes to the recruitment of monocytes to an inflammatory site.

New sterically stabilized liposomes derived from the antitumoragent hexadecylphosphocholine with reduced uptake by the mononuclearphagocyte system and improved antitumor activities were developedand tested. The bilayer of such sterically stabilizedliposomes consists of hexadecylphosphocholine, cholesterol and polyethylene glycol-linkedphosphoethanolamine. The measurement of carbon clearance in miceshows that these stabilized liposomes, in contrast toconventional alkylphosphocholine liposomes, are not largely engulfed bythe mononuclear phagocyte system. Their therapeutic activity onexperimental human breast carcinomas MaTu, MT-1 and MT-3was tested in nude mice. Especially in theMaTu models the sterically stabilized hexadecylphosphocholine liposomes resultedin significantly reduced tumor growth in comparison toconventional hexadecylphosphocholine liposomes or free hexadecylphosphocholine. The enhancedtherapeutic efficacy of sterically stabilized hexadecylphosphocholine liposomes isprobably related to the extended circulation time ofthe formulation and its accumulation in tumors.