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,
Departments of
*
Surgery,
Immunology, and
Pediatrics, Mayo Clinic, Rochester, MN 55905;
§
Department of Surgery, Duke University Medical Center, Durham, NC 27710; and
¶
Department of Surgery, University of Washington, Seattle, WA 98195
Primary immune responses are thought to be induced by dendritic
cells. To promote such responses, dendritic cells must be activated by
exogenous agonists, such as LPS, or by products of activated
leukocytes, such as TNF-
and IL-1. How dendritic cells might be
activated in the absence of exogenous stimuli, or without the immediate
presence of activated leukocytes, as might occur in immunity to tumor
cells or transplants, is unknown. We postulated that heparan sulfate,
an acidic, biologically active polysaccharide associated with cell
membranes and extracellular matrices, which is rapidly released under
conditions of inflammation and tissue damage, might provide such a
stimulus. Incubation of immature murine dendritic cells with heparan
sulfate induced phenotypic maturation evidenced by up-regulation of
I-A, CD40, 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 increased allostimulatory capacity. Stimulation of dendritic
cells with heparan sulfate induced release of TNF-, IL-1ß, and
IL-6, although the maturation 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 cells without exogenous stimuli,
thus contributing to the generation and maintenance of primary immune
responses.
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