LOW MOLECULAR WEIGHT OLIGOSACCHARIDES OF HYALURONAN POTENTLY ACTIVATE DENDRITIC CELLS

Abstract

The ECM-component hyaluronate (HA) exists physiologically as a high molecular weight polymer (HMW-HA), but is cleaved at sites of inflammation, where it will be contacted by dendritic cells (DC). To determine the effects of HA on DC, HA-fragments of different size were established. Only small HA-fragments of tetra- and hexasaccharide size (sHA), but not of intermediate size (INT-HA, MW 80-200 kDa) or HMW-HA (MW 1000-600 kDa) induced immunophenotypic maturation of human monocyte-derived DC (upregulation of HLA-DR, B7-1/2, CD83, downregulation of CD115). Likewise, only sHA increased DC-production of the cytokines IL-1β, TNFα, IL-12 as well as their allostimulatory capacity. These effects were highly specific for sHA, since they were not induced by other glycosaminoglycans (GAG's) such as chondroitinsulfate (CS) or heparansulfate (HS) or their fragmentation products. Interestingly, sHA-induced DC maturation does not involve the HA-receptors CD44 or RHAMM, since DC from CD44 deficient mice and wild type mice both responded similarly to sHA-stimulation, whereas RHAMM is not detectable in DC. These findings suggest that during inflammation interaction of DC with small HA-fragments induce DC-maturation.