Phenotypic and functional maturation of dendrite cells mediated by heparansulfate

Primary immune responses are thought to be induced by dendritic cells. To p romote such responses, dendritic cells must be activated by exogenous agoni sts, such as LPS, or by products of activated leukocytes, such as TNF-alpha and IL-1. How dendritic cells might be activated in the absence of exogeno us stimuli, or without the immediate presence of activated leukocytes, as m ight occur in immunity to tumor cells or transplants, is unknown. We postul ated that heparan sulfate, an acidic, biologically active polysaccharide as sociated with cell membranes and extracellular matrices, which is rapidly r eleased under conditions of inflammation and tissue damage, might provide s uch a stimulus. Incubation of immature murine dendritic cells with heparan sulfate induced phenotypic maturation evidenced by up-regulation of I-A, CD 40, CD54 (ICAM-1), CD80 (B7-1), and CD86 (B7-2). Dendritic cells exposed to heparan sulfate exhibited a markedly lowered rate of Ag uptake and increas ed allostimulatory capacity. Stimulation of dendritic cells with heparan su lfate induced release of TNF-alpha, IL-1 beta, and IL-6, although the matur ation of dendritic cells was independent of these cytokines. These results suggest that soluble heparan sulfate chains, as products of the degradation of heparan sulfate proteoglycan, might induce maturation of dendritic cell s without exogenous stimuli, thus contributing to the generation and mainte nance of primary immune responses.