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An aberrant production of inflammatory cytokines, with resultant febrile response, is a cardinal finding of hemophagocytic syndrome. A role of inflammatory cytokines on phagocytosis and clearance of apoptotic cells or particles has been shown, but effects of cytokines or hyperthermia on phagocytosis of viable blood cells were not fully understood. We examined effects of cytokines and hyperthermia on phagocytosis, and externalization of phosphatidylserine on the surface of phagocytosed blood cells, to clarify the pathophysiology of hemophagocytic syndrome.THP-1 macrophage cells were incubated with non-opsonized and opsonized sheep erythrocytes (SE) in the presence of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), macrophage-colony stimulating factor (M-CSF), interleukin (IL)-6, IL-10 or IL-18, and phagocytic activity was analyzed. Co-operative effect between cytokines was also examined. In addition, SE were incubated at 37 or 39°C, and phagocytic activity was analyzed. After treatment of SE with cytokine or hyperthermia, phosphatidylserine expression of the cell surface was analyzed by detecting Annexin V-positive cells.IL-6, IL-10 and IL-18 significantly increased phagocytosis of non-opsonized SE, but IFN-γ suppressed it. Phagocytosis of opsonized SE was significantly increased by any of the cytokines. IFN-γ suppressed and IL-10 enhanced phagocytic activity induced by other cytokines in non-opsonized SE, while in opsonized SE, both cytokines co-operated with other cytokines to enhance phagocytosis. Incubation of SE at a high temperature (39°C) resulted in increased phagocytic activity, as compared to SE incubated at 37°C. Cytokines and a high temperature did not increase the number of Annexin V-positive SE.IL-6, IL-10 and IL-18 can augment phagocytosis of viable blood cells, whether cells are opsonized or not. Hyperthermia also enhances phagocytosis. These in vitro data suggest that therapy for targeting cytokine (IL-6, IL-10 or IL-18) by using biologics or small molecule drugs may be beneficial for the treatment of hemophagocytic syndrome. Unlike the case of apoptotic cells, phagocytosis of viable blood cells seems to be mediated via phosphatidylserine-independent manner.