Interleukin-1 alpha and tumor necrosis factor-alpha act synergistically to stimulate production of myeloid colony-stimulating factors by cultured human bone marrow stromal cells and cloned stromal cell strains.
Caldwell, Jerry
1994
Abstract
Human bone marrow stromal cells respond to stimulation by the inflammatory cytokines interleukin-1 alpha (IL-1$\alpha$) and tumor necrosis factor-alpha (TNF$\alpha$) by producing hematopoietic growth factors (HGFs) such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). Of the two cytokines, IL-1$\alpha$ is the more potent inducer of HGF production. IL-1$\alpha$ stimulates production of G-CSF to a greater degree than GM-CSF. TNF$\alpha$, conversely, is a more potent inducer of GM-CSF than G-CSF. When stromal cell cultures were stimulated simultaneously with IL-1$\alpha$ and TNF$\alpha$, these cytokines interacted in a synergistic manner to stimulate production of GM- and G-CSF to supra-additive levels. Similarly, IL-1$\alpha$ and TNF$\alpha$ act synergistically to stimulate GM-CSF and G-CSF production by a clonally derived normal human bone marrow stromal cell strain (CDCL). The level of HGF production by CDCL cultures in response to IL-1 and TNF stimulation was several-fold greater than the levels produced by unfractionated stromal cell cultures. These data, taken together, suggest a specialized function for this subpopulation of stromal cells in the regulation and maintenance hematopoiesis within the marrow cavity. These data also suggest, perhaps, a central role for CDCL cells, or a cell population similar to CDCL cells, in the local immune response. This study also focused on cytokine trans-regulation of receptors as a potential component in the mechanism for IL-1$\alpha$/TNF$\alpha$ synergy. Our data show that IL-1$\alpha$ upregulates expression of TNF receptors (TNFRs) on the surface of CDCL cells. IL-1$\alpha$, however, does not alter TNF receptor ligand binding affinity. The increased expression of TNFRs, in response to treatment with IL-1$\alpha$, was found to be closely associated with the time course for IL-1$\alpha$/TNF$\alpha$ synergy. CDCL stromal cells express both the 55 kDa (p55) and the 75 kDa (p75) TNF receptors at a relative abundance of 60% to 40%, respectively. We have demonstrated, using TNFR antibodies, that ligand binding to the p55 receptor alone initiates the TNF signal in this in vitro system. Interestingly, however, the p75 TNFR appears to account for all of the IL-1$\alpha$ induced increase in $\sp{125}$I-TNF$\alpha$ specific binding to CDCL cells. We have concluded from these data that increased expression of TNFRs is closely associated with IL-1/TNF synergy and may be a component in the synergy mechanism, but receptor uprelation alone is insufficient for the full synergistic response.Other Identifiers
(UMI)AAI9500893
Subjects
Biology, Cell
Types
Thesis
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