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*
Division of Biochemistry, Royal Holloway University of London, Egham, Surrey, United Kingdom;
Department of Haematology, Imperial College School of Medicine, London, United Kingdom; and
School of Pharmacy, Biomedical and Physical Sciences, University of Portsmouth, Portsmouth, Hampshire, United Kingdom
Using an ELISA approach, we demonstrate that recombinant human
IL-12 (rhIL-12) binds strongly to an immobilized heparin-BSA complex.
This binding is completely displaceable with soluble heparin, IC50
0.1 µg/ml, corresponding to 10 nM. By interpolation
with our previous findings, this indicates an affinity for heparin
greater than that of antithrombin III and comparable with that of
FGF-2, two high-affinity heparin-binding proteins. Recombinant murine
IL-12 also binds strongly to heparin. The binding of rhIL-12 to heparin
shows specificity because chondroitin sulfates A and C fail to compete,
whereas chondroitin B inhibits weakly. A highly sulfated heparan
sulfate is a strong competitor, whereas other heparan sulfates show
weak or no activity. Small heparin fragments inhibit binding, although
activity decreases with size. An octasaccharide pool derived by
cleavage of heparin with nitrous acid is a significantly stronger
inhibitor than its heparinase I-derived counterpart, further indicating
structural specificity in the interaction between rhIL-12 and heparin.
The binding of recombinant p40 to heparin appears indistinguishable
from that of the IL-12 heterodimer, implying that the heparin binding
site is largely if not solely located in this subunit. These results
show for the first time that IL-12 is a heparin-binding cytokine, a
property common to the other Th1-response-inducing cytokines, IFN-
and IL-2. Our findings strongly suggest that IL-12 will tend to be
retained close to its sites of secretion in the tissues by binding to
heparin-like glycosaminoglycans, thus favoring a paracrine role for
IL-12.
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