Interleukin 1 has positive and negative regulatory effects in human long-term bone marrow culture

The observations that interleukin 1 (IL-1) increases the production of colony-stimulating factors (CSFs) by stromal cells and acts in synergy with those CSFs to stimulate the growth of progenitor cells suggest that IL-1 may have an important role in stimulating hemopoiesis. However, IL-1 also induces the synthesis by stromal cells of inhibitors of hemopoiesis including tumor necrosis factor (TNF) and prostaglandin E2. We have used long-term bone marrow culture (LTBMC) to study the effect of IL-1 on hemopoiesis in the presence of a stromal cell layer. The addition of recombinant (r)IL-1 (10 U/ml) at the initiation of the LTBMC and at each weekly feed resulted in a significant stimulation of nonadherent granulocyte-macrophage colony-forming units (CFU-GM) by week 1 and a sustained increase in colony-stimulating activity (CSA) in culture supernatants. The increased CSA activity was mainly due to granulocyte colony-stimulating factor (G-CSF) as studied by the effects of neutralizing antibodies. Following this initial stimulation, however, nonadherent layer CFU-GM became significantly suppressed by week 4, and the number of nonadherent cells was also reduced. This delayed suppression of hemopoiesis induced by continuous exposure to rIL-1 was partially abrogated by the addition of indomethacin (10(-6) M) to the cultures, but anti-TNF had no such effect and we could not detect significant TNF levels either in culture supernatants or in stromal cell extracts. Our data suggest that prostaglandin inhibitors suppress the negative feedback control of myelopoiesis induced by IL-1 and therefore may have a role in augmenting IL-1 stimulation of myelopoiesis.