Monocytes are centrally involved in both specific and nonspecific immunity by secretion of regulatory immune mediators, phagocytosis, and presentation of antigens. Recent work has shown that monocytes can phagocytose bacteria independently from Fc gamma, complement, and scavenger receptors via a CD14-mediated process. Furthermore, incorporation of cells undergoing apoptosis is also mediated by CD14. In this study we investigated the regulation of monocytic CD14-dependent phagocytosis by the immunoregulatory cytokines interleukin-10 (IL-10), interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1). In this study an in vitro human whole-blood assay was used to test regulation of CD14-dependent phagocytosis of fluorescence-labeled E. coli by IL-10, IFN-gamma, and TGF-beta1 in monocytes from healthy donors. Phagocytosis by monocytes from a patient with paroxysmal nocturnal hemoglobinuria (PNH) and its regulation by IL-10 was also investigated. Finally, regulation of monocytic incorporation of apoptotic Jurkat cells by IL-10 was analyzed. For the CD14 blockade, murine anti-CD14 IgG2a antibody RMO52 was used. We observed that IL-10, suggested to be a monocyte-deactivating cytokine, strongly increased the monocytic CD14-dependent phagocytosis of E. coli. In contrast, IFN-gamma and TGF-beta1 depressed monocytic CD14 incorporation of E. coli. Compatible with this, IL-10 upregulated CD14 expression on monocytes, whereas IFN-gamma and TGF-beta1 downregulated its expression. IL-10 also increased the monocytic CD14-dependent and -independent phagocytosis of apoptotic cells. As expected, IL-10 strongly increased the CD14-independent phagocytosis but had no influence on the CD14-dependent phagocytosis of monocytes from a PNH patient. In conclusion, our data support a general role of IL-10 for activating monocytic scavenger functions, which are at least partly mediated by CD14. This is in line with the fact that IL-10 promotes the development of monocytes to macrophages. The contrasting effects of IL-10 and IFN-gamma on monocytic CD14-dependent phagocytosis may reflect a further mechanism counterbalancing antigen-presentation and nonimmunogenic scavenging of bacterial and cellular debris. TGF-beta, however, may be an inhibitor of both systems.