Oligosaccharides of hyaluronan are potent activators of dendritic cells

The extracellular matrix component hyaluronan (HA) exists physiologically a s a high m.w. polymer but is cleaved at sites of inflammation, where it wil l be contacted by dendritic cells (DC), To determine the effects of HA on D C, HA fragments of different size were established. Only small HA fragments of tetra- and hexasaccharide size (sHA), but not of intermediate size (m.w . 80,000-200,000) or high m.w. HA (m.w. 1,000,000-600,000) induced immunoph enotypic maturation of human monocyte-derived DC (up-regulation of HLA-DR, B7-1/2, CD83, down-regulation of CD115), Likewise, only sHA increased DC pr oduction of the cytokines IL-1 beta, TNF-alpha, and IL-12 as well as their allostimulatory capacity. These effects were highly specific for sHA, becau se they were not induced by other glycosaminoglycans such as chondroitin su lfate or heparan sulfate or their fragmentation products. Interestingly, se a-induced DC maturation does not involve the HA receptors CD44 or the recep tor for hyaluronan-mediated motility, because DC from CD44-deficient mice a nd wild-type mice both responded similarly to sHA stimulation, whereas the receptor for hyaluronan-mediated motility is not detectable in DC. However, TNF-alpha is an essential mediator of sHA-induced DC maturation as shown b y blocking studies with a soluble TNFR1, These findings suggest that during inflammation, interaction of DC with small HA fragments induce DC maturati on.