Candida albicans -1,2-oligomannosides stimulate macrophage tumor necrosis factor alpha (TNF-␣) but not NO release. This stimulation desensitized macrophages by altering -1,2-oligomannoside-dependent TNF-␣ production and lipopolysaccharide-dependent TNF-␣ and NO secretion. Desensitization was not related to tyrosine phosphorylation signal transduction but was transferred by culture supernatants in which arachidonic acid derivatives were evidenced.During the course of infection, Candida albicans disregulates the immune system (8), namely by altering macrophage functions (7,20). It suppresses nitric oxide (NO) production by murine peritoneal macrophages stimulated by gamma interferon or bacterial lipopolysaccharide (LPS) (5). Although these results have pathophysiological relevance (26), the nature of C. albicans molecules responsible for either stimulation or suppression of macrophage activities has not been investigated yet.Desensitization leading to suppression of macrophage functions in response to a second stimulation is generally a property of microbial molecules which act as macrophage major stimulants (6, 31). The prototypic example of microbial stimulants presenting these activities is the bacterial LPS. Among fungi, the cryptococcal capsular polysaccharide has been shown to display down-regulating activities concerning tumor necrosis factor alpha (TNF-␣) and interleukin 1 (IL-1) secretion (14, 28).C. albicans yeast cells stimulate TNF-␣ production (12, 16), and different C. albicans-derived molecules have been shown to maintain these capacities (9,11,27). All these molecules display a polysaccharidic moiety presenting -1,2-oligomannosides (25), a special type of sugars first described in the acidlabile fraction of the C. albicans cell wall phosphopeptidomannan (22). The -1,2-oligomannosides are able per se to stimulate TNF-␣ production (13). This stimulation depended on the oligomer size, and the mannotetraose was the minimal C. albicans-derived molecular entity displaying TNF-␣-inducing properties. With the aim of exploring the molecular mechanisms responsible for down-regulation of macrophage functions by C. albicans, we used this C. albicans-derived -1,2 mannotetraose in a series of experiments (whose principle is shown in Fig. 1) with the J774 macrophage cell line.Cells were incubated with 50 M -1,2-mannotetraose purified from the cell wall of the VW32 strain of C. albicans (serotype A) as previously described (13). The effect on cell stimulation was first compared to that obtained with 1 g of LPS per ml from Escherichia coli (0111B4). The cell response was examined through the measurement in the cell-free supernatants of TNF-␣ by using the L929 lytic bioassay (13). Comparable amounts and kinetics of TNF-␣ production were obtained with both stimuli: cytokine production peaked after 4 to 5 h of stimulation with values of 6.6 Ϯ 3.0 and 6.7 Ϯ 3.0 ng/ml upon -1,2-oligomannoside and LPS stimulation, respectively, and decreased to an undetectable amount after 12 to 15 h. LPS-dependent cytokine indu...