Increased C3 production in human monocytes after stimulation with Candida albicans is suppressed by granulocyte-macrophage colony-stimulating factor

Abstract

Activation of the complement system is an important part of host resistance against fungal infections. When human monocytes, cultured for 2 days or more, were treated in vitro with Candida albicans for 24 h, an enhancement of their biosynthesis of the complement components C3 and factor B was found. However, when C. albicans was administered to freshly isolated monocytes, a consistent stimulation of factor B biosynthesis occurred, while the C3 production was increased in about 50%o of the donors. C. albicans also induced the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) from the cultured cells, apparently in larger amounts in the donors in whom no stimulation of C3 production was found. An antibody to GM-CSF administered with the yeast at the initiation of the monocyte culture caused an increase in the C3 production. Furthermore, when monocytes were treated with recombinant human GM-CSF either at the same time as or 4 days prior to the addition of C. albicans, the increase in C3 production was suppressed or neutralized, while factor B biosynthesis was unaffected. Taken together, these results indicate that monocytes respond to C. albicans with an increased production of complement factors. This may be an important mechanism both for opsonization of the fungus and for initiation of an inflammatory reaction. At an inflammatory site, this complement response may be suppressed by locally produced GM-CSF.Candida albicans is an opportunistic pathogen which may cause severe disseminated disease in immunocompromised patients (32). The host defense against fungal infections is accomplished by phagocytes, including monocytes/macrophages, in addition to cell-mediated and humoral immune mechanisms (36). Opsonization of C. albicans by complement factors and immunoglobulins enhances phagocytosis and intracellular killing of the yeast by the phagocytes (33). Monocytes/macrophages are the main extrahepatic source of complement factors (6, 20, 22, 41), and they provide all the components necessary for local complement activation. Factor B, the initial component of the alternative pathway, is activated after direct contact with microorganisms and other foreign agents. C3 is a key component in the complement system, as it represents a joining site for the classical and alternative pathways to a common terminal pathway. The cleavage products obtained during complement activation are potent anaphylatoxins, chemotaxins, and opsonins, which are important in the local inflammatory reaction (19).The monocyte production of complement factors is modulated by several physiological and foreign substances, such as interferons (18), immuncomplexes (27), and lipopolysaccharide (LPS) (38, 39). The ingestion of streptococci has been shown to stimulate C3 production in macrophage-like cell lines (16). Phagocytosis may stimulate the monocytes/ * Corresponding author. Electronic mail address: a.k.hogasen@ rh.uio.no(INTERNET).

Herpes simplex virus type 1 inhibits in vitro differentiation and selected functions of human blood‐derived monocytes

“…In fact there was a considerable donor-to-donor variation in several of the parameters measured. Similar variations between donors have been found in several cell populations in response to external stimuli (7, 23,25). It is therefore not a surprising finding; it indicates rather that host factors play an important role in the response to the viral infection.…”

The effect of human cytomegalovirus on selected functions of peripheral blood monocytes

“…It is well known that the clinical appearance of an infection with HCMV is not necessarily correlated with the amount of virus found in the blood or in the affected organs (1 6). Similarly, also the specified cell populations obtained from different donors may show a variable reaction to an external stimulus (19,34,46). It is therefore not entirely surprising that we found considerable differences in the reaction pattern of cells from different donors.…”

Secretion of the C3 component of complement by peritoneal cells cultured with encapsulated Cryptococcus neoformans

“…Gamma interferon has also been reported to downregulate the C3 mRNA response (11). Granulocyte-macrophage CSF (GM-CSF) downregulates C3 secretion elicited by endotoxin and by Candida species (18), and GM-CSF mRNA expression is inhibited in NK cells exposed to cryptococci (27a). Because the capsular polysaccharide can induce expression of IL-1 and IL-6 (32) and potentially down-regulate GM-CSF expression in vivo, the combination of these factors could allow cryptococci with large capsules to significantly upregulate synthesis of C3 and possibly other complement components.…”