Hyperhomocysteinemia is a risk factor for atherosclerosis and thrombosis. The aim of this study was to analyze if exposure of monocytic cells to increased levels of homocysteine (HCY) induces the accumulation of inflammatory mediators. Interleukin (IL)-6 production by monocytic cell line Mono Mac 6 (MM6) was 1.7-fold increased in the presence of 50 micromol/l HCY and 3.5-fold with 200 micromol/l HCY. Incubation with homocystine resulted in a comparable dose-dependent increase, but neither cysteine nor methionine stimulated IL-6 accumulation. Elevated homocysteine concentrations did not affect the production of IL-8 and monocytic chemotactic protein-1 (MCP-1) in MM6. Furthermore, lipopolysaccharide (LPS) stimulation of MM6, cultured with elevated HCY (200 micromol/l) levels, resulted in a 3.5-fold increased response after 18 h, whereas no effect on LPS-induced IL-8 and MCP-1 response was observed. In conclusion, increased concentrations of homocysteine induce IL-6 accumulation in monocytic cells. After treatment with homocysteine, monocytic cells become more susceptible to endotoxin. This study is in favor of an association between homocysteine and monocytic IL-6 production.