Production of granulocyte colony-stimulating factor by THP-1 cells in response to retinoic acid and phorbol ester is mediated through the autocrine production of interleukin-1.

The human monocytic leukemic cell line, THP-1, which differentiates toward macrophages in response to phorbol 12-myristate 13-acetate (PMA) was investigated for its ability to produce granulocyte colony-stimulating factor (G-CSF). G-CSF protein was neither produced during PMA-induced differentiation nor in response to retinoic acid (RA) alone. However, when combined, PMA and RA synergistically stimulated G-CSF production with optimal effect observed at 10(-7)M for both PMA and RA. The synergistic interaction between PMA and RA on G-CSF production appeared to be mediated primarily through production of interleukin-1 beta (IL-1 beta) since neutralization of IL-1 beta activity inhibited about 80% of G-CSF production. It has been previously reported that IL-1 potently synergizes with RA to stimulate G-CSF production by THP-1 cells pretreated with PMA Using synthetic ligands to RA receptors (RAR) and retinoid X receptors (RXR) that selectively bind and activate RAR-RXR and RXR-RXR dimers respectively, we showed that the ability of RA to synergize with IL-1 was signaled through RAR-RXR heterodimer pathway. Finally, we demonstrated that RA can also enhance IL-1-induced G-CSF production in primary monocytes of human peripheral blood.