Sialoadhesin is a macrophage-restricted member of the Ig superfamily that mediates adhesion with lymphoid and myeloid cells. It is expressed on a subpopulation of macrophages in lymphoid tissues and in chronic inflammation (e.g., during autoimmune diseases). We have studied the regulation of sialoadhesin expression in vitro and show that glucocorticoids (GC) induce sialoadhesin expression on freshly isolated rat macrophages and the rat macrophage cell line R2. The cytokines IFN-beta, IFN-gamma, IL-4, and LPS, although unable to induce sialoadhesin expression by themselves, were able to enhance GC-mediated induction of sialoadhesin. Sialoadhesin expression was functional as shown by cell adhesion assays with human RBCs. Northern blotting experiments indicated that regulation predominantly occurred at the mRNA level. Comparison of the different combinations of GC and cytokines/LPS revealed differences in the level of GC-dependent enhancement of sialoadhesin expression, with IFN-beta and IL-4 being more potent than IFN-gamma and LPS. Moreover, the effects of IFN-gamma and LPS could be reproduced by priming, whereas IFN-beta and IL-4 were required simultaneously with GC. The regulation of sialoadhesin expression was mediated by the GC receptor, and not by mineralocorticoid receptor, as shown by inhibition experiments with specific antagonists. Finally, it is demonstrated that macrophages in the adrenal gland, the major site of endogenous GC production, express sialoadhesin. This study demonstrates that GC act as a primary inducer of sialoadhesin expression on rat macrophages, and that the response can be enhanced by IFN-beta, T cell-derived cytokines, or LPS.