Interleukin-1 alpha upregulates tumor necrosis factor receptors expressed
by a human bone marrow stromal cell strain: implications for cytokine
redundancy and synergy
J Caldwell and SG Emerson
Cell and Molecular Biology Program, University of Michigan, Ann Arbor, USA.
To explore the biochemical and physiologic basis of the overlapping effects
of interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha
(TNF-alpha) 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-1 alpha and TNF alpha 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-1
alpha induces a 300% increase in the expression of TNF receptors. IL-1
alpha induction of TNF receptors reaches a peak after 6 hours and gradually
returns to baseline level by 24 hours. IL-1 alpha does not affect TNF
receptor ligand binding affinity. A kinetic study comparing IL-1/TNF
synergistic induction of growth factor secretion with IL-1 alpha induction
of TNF receptors shows that these events occur in parallel. In contrast
with the induction of TNF receptors by IL-1 alpha, treatment with TNF alpha
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-1
alpha/TNF alpha-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-1 alpha cross-induction of TNF receptors may
contribute to the biochemical mechanisms underlying the synergistic
stimulation of G-CSF and GM-CSF production by IL-1 alpha and TNF alpha.
Volume 86,
Issue 9,
pp. 3364-3372,
11/01/1995
Copyright © 1995 by The American Society of Hematology
