Regulation of murine splenocyte responses by heparan sulfate

Heparan sulfate is a biologically active glycosaminoglycan found in abundance in endothelium, epithelium, and connective tissues. Although heparan sulfate is an important part of the environment in which immune cells function, its effects on the immune system are largely unknown. When present during the first 24 h of an MLC consisting of MHC disparate murine splenocytes, heparan sulfate had a marked stimulatory effect on the proliferative response to alloantigens. Heparan sulfate also augmented the splenocyte response to suboptimal concentrations of the mitogens Con A, anti-CD3 mAb, and ionomycin. The stimulatory action of heparan sulfate was mediated, at least in part, by increased production of IL-1, because the increased splenocyte proliferation induced by heparan sulfate was substantially inhibited by anti-murine IL-1 alpha-antibodies. In contrast to these stimulatory effects, when heparan sulfate was added to MLC 48 to 72 h after onset, decreased splenocyte proliferation was observed. This inhibitory action was mediated by an increase in PGE2 production; the inhibitory effect could be abrogated with indomethacin. The fact that heparan sulfate is present on cells such as endothelial cells with which T cells interact and is released during activation of endothelial cells (thus making it available in soluble form to cells in the immune response) may allow heparan sulfate to play an important role in modulating cell-mediated immune responses in vivo.