To clarify the mechanisms that cause elevation of plasma fibrinogen levels in diabetes, we first examined the effect of hyperglycemia on the production of interleukin 6 (IL-6) and tumor necrosis factor (TNF) by cultured human peripheral blood monocytes. Monocyte-enriched fractions isolated from 20 healthy volunteers were incubated with 11 mmol/l glucose, 33 mmol/l glucose, or mannitol as an osmolar control for 6 or 24 h. After 6 h of incubation, IL-6 and TNF-alpha mRNA levels were analyzed by reverse transcription and polymerase chain reaction. In addition, after 24 h of incubation, IL-6 and TNF-alpha immunoreactivity in the culture medium was measured by enzyme-linked immunoassay. Both IL-6 and TNF-alpha mRNA levels and immunoreactivity were significantly increased by treatment with 33 mmol/l glucose compared with treatment with 11 mmol/l glucose or 11 mmol/l glucose with 22 mmol/l mannitol. In addition, preincubation of the cells with an anti-TNF monoclonal antibody (mAb) blocked the stimulatory effect of 33 mmol/l glucose on IL-6 synthesis and secretion. Second, we examined the ability of conditioned media from human peripheral blood monocytes to stimulate beta-fibrinogen mRNA synthesis in HepG2 cells. The conditioned medium from monocytes treated with 33 mmol/l glucose increased beta-fibrinogen mRNA levels. The results of this study demonstrate that hyperglycemia stimulated IL-6 and TNF synthesis and secretion by human peripheral monocytes in vitro and that the IL-6 response to hyperglycemia may be mediated by TNF. Furthermore, hyperglycemia may increase fibrinogen levels through stimulation of peripheral monocytes. These results suggest that hyperglycemia may cause hyperfibrinogenemia in diabetic patients through an IL-6-dependent and TNF-dependent mechanism.