Activated human monocytes are a source of numerous beta-chemokines. The present study was conducted to determine whether these cells produce the human beta-chemokine I-309 and to compare the induction requirements of I-309 to those of other beta-chemokines. We demonstrate that appropriately stimulated adherence-purified human peripheral blood monocytes express I-309 transcripts and secreted I-309 protein. Two stimuli, immobilized IgG and lipopolysaccharide (LPS), synergize strongly to induce I-309 gene expression. We further demonstrate that the production of endogenous interleukin (IL)-1alpha plays a crucial role in I-309 induction. Thus, neutralization of endogenous IL-1alpha using an anti-IL-1alpha antiserum inhibits the induction of I-309 transcripts in response to stimulation with immobilized IgG and LPS, and exogenous IL-1alpha or IL-1beta induces I-309 transcripts in monocytes stimulated with immobilized IgG. Immobilized IgG and LPS have the opposite effect on monocyte chemoattractant protein-1 (MCP-1) gene expression, in that the induction observed with either stimulus alone is diminished using the two stimuli in combination. Furthermore, endogenous and exogenous IL-1 can be either stimulatory or inhibitory for MCP-1 gene expression depending on other signals delivered to the monocytes. Immobilized IgG and LPS synergize to induce macrophage inflammatory protein-1alpha transcripts, but endogenous IL-1 does not play a significant role. Thus, each of these beta-chemokine genes is under distinct regulatory control in human monocytes.