REGULATION OF I-309 GENE-EXPRESSION IN HUMAN MONOCYTES BY ENDOGENOUS INTERLEUKIN-1

Activated human monocytes are a source of numerous beta-chemokines. Th e present study was conducted to determine whether these cells produce the human beta-chemokine I-309 and to compare the induction requireme nts of I-309 to those of other beta-chemokines. We demonstrate that ap propriately stimulated adherence-purified human peripheral blood monoc ytes 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 producti on of endogenous interleukin (IL)-1 alpha plays a crucial role in I-30 9 induction. Thus, neutralization of endogenous IL-1 alpha using an an ti-IL-1 alpha antiserum inhibits the induction of I-309 transcripts in response to stimulation with immobilized IgG and LPS, and exogenous I L-1 alpha or IL-1 beta induces I-309 transcripts in monocytes stimulat ed with immobilized IgG. Immobilized IgG and LPS have the opposite eff ect on monocyte chemoattractant protein-1 (MCP-1) gene expression, in that the induction observed with either stimulus alone is diminished u sing the two stimuli in combination. Furthermore, endogenous and exoge nous IL-1 can be either stimulatory or inhibitory for MCP-1 gene expre ssion depending on other signals delivered to the monocytes. Immobiliz ed IgG and LPS synergize to induce macrophage inflammatory protein-la transcripts, but endogenous IL-1 does not play a significant role. Thu s, each of these beta-chemokine genes is under distinct regulatory con trol in human monocytes.