GM-CSF and IL-3 activities in schistosomal liver granulomas are controlled by stroma-associated heparan sulfate proteoglycans.

Connective tissue cells (myofibroblasts) from liver inflammatory granulomatous reactions to schistosome eggs are able to sustain a long-term proliferation of myeloid cells, both in vivo and in vitro. We have addressed the question of the molecular mechanisms involved in control of this extramedullar stroma-dependent production of inflammatory cells. Heparan sulfate proteoglycans (HSPGs) were purified from granuloma-derived connective tissue cells and bound to plastic or collagen substrate. Their ability to bind recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), to stimulate proliferation of the FDC-P1 myeloid cell lineage, and to modify growth factor activity was monitored. The specificity of this stroma cell-derived glycosaminoglycan interaction with the myeloid growth factors was analyzed by comparing other glycosaminoglycans and sulfated polysaccharides. HSPGs could act as an artificial myelopoietic stroma; they were both required and sufficient for binding and presenting GM-CSF and IL-3 in biologically active form. Moreover, they were able to mediate an increase in the specific growth-promoting activity of GM-CSF and IL-3. This was specific for stroma-derived heparan sulfate and heparin, since heparan sulfate derived from other cells, other glycosaminoglycans and related molecules had no effect. These results indicate that HSPGs can stimulate and control the in situ proliferation of myeloid cells, modifying in both quantitative and qualitative terms the composition of inflammatory cell infiltrates in hepatic granulomas.