Interleukin-1α upregulates tumor necrosis factor receptors expressed by a human bone marrow stromal cell strain: Implications for cytokine redundancy and synergy

Abstract

To explore the biochemical and physiologic basis of the overlapping effects of interleukin-1α (IL-1α) and tumor necrosis factor α (TNF-α) on myeloid cytokine production, we have studied the dynamics of granulocyte colony-stimulating factor (G-CSF) and granulocyte-monocyte colony-stimulating factor (GM-CSF) production as well as IL-1 receptor and TNF receptor expression in a clonally derived bone marrow stromal cell strain (CDCL). IL- 1α and TNFα act in a synergistic manner to stimulate G-CSF and GM-CSF production by CDCL, resulting in an increase in CSF secretion that is 250- fold greater than that observed with either cytokine alone. This synergism in protein secretion is paralleled by synergistic increases the steady-state level of GM- and G-CSF mRNA, with supra-additive levels achieved by 24 hours. Coincident with this synergistic induction of myeloid CSFs, treatment of CDCL cells with IL-1α induces a 300% increase in the expression of TNF receptors. IL-1α induction of TNF receptors reaches a peak after 6 hours and gradually returns to baseline level by 24 hours. IL-1α does not affect TNF receptor ligand binding affinity. A kinetic study comparing IL-1/TNF synergistic induction of growth factor secretion with IL-1α induction of TNF receptors shows that these events occur in parallel. In contrast with the induction of TNF receptors by IL-1α, treatment with TNFα has no effect on either the number of IL-1 receptors expressed by CDCL cells or IL-1 receptor ligand binding affinity. Brief treatment of IL-1α/TNFα-stimulated CDCL cells with cycloheximide before receptor induction reduces the synergistic increase in growth factor mRNA by 40% to 60% compared with cells not treated with CHX. Taken together, these results raise the possibility that IL-1α cross- induction of TNF receptors may contribute to the biochemical mechanisms underlying the synergistic stimulation of G-CSF and GM-CSF production by IL- 1α and TNFα.