Heparin and heparan sulfate bind interleukin-10 and modulate its activity.
AffiliationCRC Molecular Biology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Withington, Manchester, UK. email@example.com
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AbstractGlycosaminoglycans (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-beta, IL-7, and interferon-gamma. 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, K(d), 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 IC(50) values of 100 to 500 microg/mL. Considerably higher concentrations of dermatan sulfate and chondroitin 4-sulfate were required with an IC(50) of 2,000 to 5,000 microg/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. (Blood. 2000;96:1879-1888)
CitationHeparin and heparan sulfate bind interleukin-10 and modulate its activity. 2000, 96 (5):1879-88 Blood
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