IL‐1α and TNFα act synergistically to stimulate production of myeloid colony‐stimulating factors by cultured human bone marrow stromal cells and cloned stromal cell strains

Abstract

Human bone marrow stromal cells respond to stimulation by the monokines IL-1 and TNF by producing colony-stimulating factors such as GM-CSF and G-CSF. In this study we show that IL-1 alpha and TNF alpha act synergistically to stimulate GM-CSF and G-CSF production by cultured marrow stromal cells. We further show that IL-1 alpha and TNF alpha synergistically stimulate production of GM-CSF and G-CSF by a clonal stroma-derived cell strain. Although IL-1 and TNF share many of the same biological activities, we show that IL-1 alpha and TNF alpha have an unequal ability to induce myeloid-CSF production by both cultures, with IL-1 alpha being the more potent inducer. We found that induction by IL-1 alpha and TNF alpha was independent of cell proliferation. The effect of IL-1 alpha and TNF alpha on production of the two myeloid-CSFs by the clonal cells was significantly greater than the unfractionated passaged stromal cultures, having the greater effect on G-CSF production. The clonally derived stromal cells constitutively produced colony-stimulating activity, in particular GM-CSF, at levels easily detected by ELISA. These findings show that, in addition to the overlapping and additive activities of IL-1 alpha and TNF alpha, they can interact synergistically. Our findings further suggest that a small subpopulation of stroma cells may be the major producer of G-CSF in the marrow microenvironment during immune response.