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- W1980551454 abstract "Upon activation, mononuclear phagocytes (MØ) play key roles in the development of septic shock and multiple host immune responses, but details of the regulation of MØ activation are little understood. We recently showed that the physiologic anticoagulant molecule, activated protein C (APC), blocks responses of human blood MØ, alveolar MØ, or THP-1 cells induced by LPS, IFN-γ, or PMA, including TNF-α production and down-regulation of several LPS binding-related proteins. We now report a possible mechanism of action through inhibition of the rapid intracellular calcium signaling that occurs at the onset of MØ activation, and characterization of a specific MØ receptor for APC. Flow cytometry studies using Fluo-3 showed that MØ activation by Fc-receptor cross-linking or rIFN-γ caused a rapid increase in free intracellular calcium, a primary event in multiple signal transduction pathways, which was blocked by pretreatment with APC. Consistent with this, addition of APC inhibited PHA-induced T cell proliferation in a dose- and time-dependent manner. Peak suppression (>70%) required addition of APC within the first hour of 72 hr cocultures of MØ and lymphocytes, and proliferative responses were not restored by addition of IL-2 or TNF-α. Biochemical studies showed that 125I-labeled APC bound specifically to MØ in a time-dependent and saturable manner. Scatchard analysis indicated there were 180,690 binding sites for APC per cell, which were of high affinity (Kd value of 12.9 nM). Binding of 125I-APC was doubled by activation of MØ with LPS, and bound APC was not displaced by the zymogen, protein C (PC), or by enzymatically inactive (diisopropyl fluorophosphate- or PPACK-treated) APC, indicating an absolute requirement for the active site of APC in its binding to MØ. APC binding was blocked by a polyclonal Ab to human PC/APC, but not by protein S, factor Va or Xa, or a polyclonal antithrombomodulin antibody. When 125I-APC was crosslinked to its receptor, immunoprecipitated and analyzed by SDS-PAGE under reducing conditions, a covalent complex (110-115 kD) of 125I-APC (62 kD) and its receptor was seen. In addition, a MØ membrane protein of 50-55 kD, as determined by SDS-PAGE, was affinity-purified using an APC-Affigel column, and confirmed by ligand binding. Taken together, our findings document the presence of a MØ surface receptor for APC, which appears distinct from a recently described endothelial receptor for PC and APC, and which may be involved in the inhibitory effects of APC on activation of human MØ, including MØ-dependent T cell proliferation." @default.
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- W1980551454 date "1995-12-01" @default.
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- W1980551454 title "BINDING OF ACTIVATED PROTEIN C TO A SPECIFIC RECEPTOR ON HUMAN MONONUCLEAR PHAGOCYTES INHIBITS INTRACELLULAR CALCIUM SIGNALING AND MONOCYTE-DEPENDENT PROLIFERATIVE RESPONSES1,2" @default.
- W1980551454 doi "https://doi.org/10.1097/00007890-199560120-00026" @default.
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