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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1879-1888
IMMUNOBIOLOGY
Heparin and heparan sulfate bind interleukin-10 and modulate
its activity
Shahram Salek-Ardakani,
John R. Arrand,
David Shaw, and
Mike Mackett
From the CRC Molecular Biology Group, Paterson
Institute for Cancer Research, Christie Hospital NHS Trust, Withington,
Manchester, UK.
Glycosaminoglycans (GAG) are a group of negatively charged
molecules that have been shown to bind and directly regulate the bioactivity of growth factors and cytokines such as basic fibroblast growth factor, transforming growth factor- , IL-7, and
interferon- . The ability of GAG to interact with human IL-10
(hIL-10) and the effect of these interactions on its biologic activity
were analyzed. It was demonstrated by affinity chromatography that
hIL-10 binds strongly to heparin-agarose at physiological pH.
Biosensor-based binding kinetic analysis indicated an equilibrium
dissociation constant, Kd, of 54 nmol/L for
this interaction. Human IL-10 stimulated CD16 and CD64 expression on
the monocyte/macrophage population within peripheral blood mononuclear
cells, with optimal concentrations between 1 and 10 ng/mL. Soluble
heparin, heparan sulfate, chondroitin sulfate, and dermatan sulfate
were shown to inhibit the hIL-10-induced expression of CD16 and CD64
in a concentration-dependent manner. Heparin and heparan sulfate were
most effective with IC50 values of 100 to 500 µg/mL.
Considerably higher concentrations of dermatan sulfate and chondroitin
4-sulfate were required with an IC50 of 2000 to 5000 µg/mL, whereas chondroitin 6-sulfate was essentially inactive. The
antagonistic effect of heparin on hIL-10 activity was shown to be
dependent on N-sulfation, inasmuch as
de-N-sulfated heparin had little or no inhibitory effect on
the IL-10- induced expression of CD16, whereas the effect of
de-O-sulfated heparin was comparable to that of unmodified
heparin. Furthermore, the inhibition of cell-bound proteoglycan
sulfation reduced the hIL-10-mediated expression of CD16 molecules on
monocytes/macrophages. Taken together, these findings support the
hypothesis that soluble and cell-surface GAG and, in particular, their
sulfate groups are important in binding and modulation of hIL-10 activity.
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