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Stimulation of interleukin-6 and prostaglandin E2 secretion from peritoneal
macrophages by polymers of albumin
E Shacter, GK Arzadon and JA Williams
Laboratory of Genetics, National Cancer Institute, National Institutes of
Health, Bethesda, MD 20892.
Interleukin-6 (IL-6) is a multifunctional cytokine that is elevated in vivo
during acute infection, chronic inflammation, and some hematopoietic
malignancies. To understand how IL-6 becomes elevated in vivo, it is
important to identify factors that can stimulate its secretion from
effector cells. We found that commercial preparations of bovine serum
albumin (BSA) stimulated murine macrophages to secrete high levels of IL-6.
In fact, BSA was at least as potent as bacterial lipopolysaccharide (LPS)
in stimulating IL-6 production. Stimulation was clearly visible at
concentrations as low as 20 micrograms/mL and reached saturation at 0.5 to
1 mg/mL albumin, at which concentration 1.1 x 10(6) oil-elicited
macrophages produced 6,000 +/- 700 B9 units of IL-6 in an overnight
incubation. Prostaglandin E2 production was induced by the same
concentrations of BSA. Both resident and oil- elicited peritoneal cells
were responsive to the albumin. The stimulatory activity did not derive
from contamination of the protein with Escherichia coli LPS; when compared
directly with LPS, the response to BSA was more rapid, had a higher
amplitude, and was not inhibitable by polymyxin B. In addition, macrophages
isolated from C3H/HeJ mice, which have an inherited defect in their ability
to respond to LPS, secreted IL-6 in response to BSA but not to LPS. The
stimulatory activity was stable to heat, mild acid, and
reduction/alkylation and copurified with albumin on Cibachron Blue agarose
(Sigma, St Louis, MO) and anti-albumin immunoaffinity chromatography.
Comparison of different sources and preparations of albumin showed
differences in the levels of IL-6-inducing activity; three different lots
of commercial fatty acid-free BSA and one lot of polymer-enhanced BSA
stimulated IL-6 secretion by more than 100-fold over basal levels whereas
other preparations showed more limited activity. A sample of BSA that was
active in vitro caused a marked elevation of IL-6 when injected into BALB/c
mice, thus demonstrating inflammatory activity in vivo. When the albumin
preparations were fractionated by ion exchange and gel filtration
chromatography and then analyzed by sodium dodecyl sulfate-gel
electrophoresis and Western blot immunoassay, it was found that the
IL-6-inducing activity resided in high molecular weight polymers of
albumin. The ability of albumin polymers to stimulate IL-6 production
represents a novel mechanism for modulation of this cytokine.
Volume 82,
Issue 9,
pp. 2853-2864,
11/01/1993
Copyright © 1993 by The American Society of Hematology
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