Cloning and expression of murine interleukin-1 receptor antagonist in
macrophages stimulated by colony-stimulating factor 1
H Matsushime, MF Roussel, K Matsushima, A Hishinuma and CJ Sherr
Department of Tumor Cell Biology, St Jude Children's Research Hospital,
Memphis, TN 38105.
Colony-stimulating factor 1 (CSF-1) can act on mature macrophages to
modulate their production of inflammatory cytokines. A cDNA encoding the
interleukin-1 receptor antagonist (IL-1Ra) was cloned by subtractive
hybridization from a CSF-1-stimulated murine macrophage cell line,
sequenced, and expressed in mammalian and bacterial cells. Mouse IL-1Ra is
a 22-Kd glycoprotein that is 76% identical to its human counterpart, shows
considerably less similarity to IL-1 alpha and IL-1 beta, and competes with
IL-1 alpha for binding to the type I IL-1 receptor normally expressed on T
cells and fibroblasts. CSF-1 treatment of mouse bone marrow-derived
macrophages led to a rapid and sustained increase in IL-1Ra mRNA during the
G1 phase of the cell cycle as well as to increases in mRNAs encoding IL-1
alpha and IL-1 beta. Cycloheximide inhibited CSF-1-induced IL-1 alpha mRNA
synthesis, but augmented IL-1 beta mRNA production and did not affect
induction of IL- 1Ra mRNA. No IL-1Ra mRNA was observed in CSF-1-stimulated
mouse fibroblasts engineered to express CSF-1 receptors, demonstrating that
its regulation depends on cell context and can be dissociated from the
proliferative response. In agreement, bacterial lipopolysaccharide, a
nonmitogenic activator, also induced IL-1Ra and IL-1 mRNAs in macrophages.
Unlike IL-1 alpha and beta, IL-1Ra contains a signal peptide. The kinetics
of its induction and its ability to gain access to the secretory
compartment imply that IL-1Ra may be secreted more efficiently than IL-1,
and suggest that macrophages both positively and negatively regulate the
IL-1 response.
Volume 78,
Issue 3,
pp. 616-623,
08/01/1991
Copyright © 1991 by The American Society of Hematology
