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Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of
circulating IL-1 receptor antagonist and soluble tumor necrosis factor
receptor p55
H Tilg, E Trehu, MB Atkins, CA Dinarello and JW Mier
Department of Medicine, New England Medical Center, Boston, MA 02111.
The aim of this study was to investigate whether interleukin (IL)-6 induces
the production of IL-1 and tumor necrosis factor (TNF) antagonists. Serial
plasma samples were obtained from cancer patients participating in phase I
and II trials of recombinant IL-6 administered as a 120-hour continuous
intravenous (IV) infusion. Plasma IL-1 receptor antagonist (IL-1Ra) and
soluble TNF receptor p55 (TNFsRp55) levels were measured by specific
radioimmunoassays (RIAs). IL-1Ra levels increased rapidly, reaching peak
values (9.6 +/- 1.7 ng/mL) within 2 to 4 hours of beginning treatment.
Thereafter, levels promptly declined, reaching near baseline within 24
hours despite continuation of IL-6. TNFsRp55 plasma levels increased within
4 to 8 hours after initiating treatment and increased progressively
throughout the duration of therapy. IL-1 beta and TNF-alpha plasma levels
were below the detection limit in all samples tested. Peripheral blood
mononuclear cells (PBMC) exposed to IL-6 produced only small amounts (1.56
+/- 0.3 ng/mL) of IL-1Ra, even in the presence of exogenous soluble IL-6
receptor (gp80). TNFsRp55 levels measured in the supernatants of IL-6-
stimulated PBMC were below the detection limit of the assay. Macrophages
generated by culturing monocytes in granulocyte-macrophage
colony-stimulating factor (GM-CSF) were much more responsive to IL-6 than
freshly isolated unfractionated or adherent PBMC and synthesized almost as
much IL-1Ra when stimulated with IL-6 as with endotoxin. These results
suggest that the antinflammatory properties of IL-6 may be due; in part, to
the induction of IL-1Ra synthesis and the release of soluble TNF receptors.
Our findings also suggest that tissue macrophages may be an important
source of IL-6-induced IL-1Ra.
Volume 83,
Issue 1,
pp. 113-118,
01/01/1994
Copyright © 1994 by The American Society of Hematology
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