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Regulation of cytokine release from mononuclear cells by the iron- binding
protein lactoferrin
SP Crouch, KJ Slater and J Fletcher
Medical Research Centre, City Hospital, Nottingham, UK.
The iron-binding protein lactoferrin (Lf) is a constituent of neutrophil
secondary granules and is discharged into the surrounding medium when
neutrophils are activated. Lf released from neutrophils phagocytosing
opsonized particles inhibits proliferation of mixed lymphocyte cultures
(MLC) and has also been shown to inhibit granulopoiesis, suppress antibody
production, and regulate natural killer cell activity. All of these
processes are controlled by cytokines, suggesting that Lf may modulate
immune responses by inhibiting cytokine activity. When MLC were cultured in
round-bottomed wells to crowd the cells together, Lf, 50% saturated with
iron, inhibited both proliferation and interleukin-2 (IL-2) release into
the supernatants. Inhibition was concentration-dependent and lost at
concentrations of Lf greater than 10(-12) mol/L. Lf at 10(-10) mol/L
inhibited release of tumor necrosis factor-alpha (TNF) and interleukin- 1
beta (IL-1) into MLC supernatants, as well as inhibiting IL-2 release. TNF
in the supernatant was significantly reduced at 5 and 24 hours, becoming
less and losing significance by 72 hours. IL-1 in the supernatant was not
significantly reduced at 5 and 24 hours, becoming significant at 48 and 72
hours. IL-2 was significantly reduced at 48 and 72 hours and followed the
same time course as proliferation. Inhibition was blocked by specific
antiserum to Lf, but not by a preimmune serum. Lf, 10(-10) mol/L, also
inhibited the production of TNF (49.15% +/- 7.98%; n = 10, P = .032) and
IL-1 (42.67% +/- 6.72%; n = 6, P = .032) from endotoxin-stimulated
mononuclear cells. As with MLC, inhibition was dose-dependent and abrogated
by specific antiserum. Lf did not block the biological action of TNF, IL-1,
or IL-2 in specific assays using cytokine-sensitive cell lines. These data
suggest that Lf, released from activated neutrophils, acts as a negative
feedback mechanism to prevent recruitment and activation of leukocytes in
sites of inflammation.
Volume 80,
Issue 1,
pp. 235-240,
07/01/1992
Copyright © 1992 by The American Society of Hematology
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