The S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor MDL 28,842 has been demonstrated to be a potent inhibitor of T-cell activation, both in vitro and in vivo. Although the inhibition of T cells in vitro was independent of macrophages, the direct effect of MDL 28,842 on macrophages is unknown. In this report the effects of MDL 28,842 on macrophage cytokine production, cell-surface antigen expression, and antigen processing and presentation were examined. Lipopolysaccharide (LPS) stimulation of IL-1 synthesis by peritoneal macrophages was not effected by MDL 28,842 using cells obtained from B10.A and B10.B mice and weakly inhibited using cells from BALB/C mice (IC50 > 10 microM). In contrast, TNF-alpha synthesis by BALB/C macrophages was inhibited by MDL 28,842 with an IC50 < 0.1 microM. B10.A and B10.B macrophages did not produce detectable TNF-alpha in response to LPS in this system. Treatment with 1-10 microM MDL 28,842 resulted in a modest decrease in major histocompatibility complex class II (MHC-II) determinant expression by Interferon-gamma-activated macrophages. The expression of other cell-surface markers was not altered in the presence of MDL 28,842. The processing of antigen and its presentation by MHC class-II-positive macrophages to a T-cell hybridoma was also not affected by incubation with MDL 28,842.)