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GM-CSF and IL-3 activities in schistosomal liver granulomas are controlled by stroma-associated heparan sulfate
1Departamento de Bioquímica, Instituto de Química, Universidade Federaldo Rio de Janeiro, Brasil.
Abstract:
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.
Insights
Heparan sulfate proteoglycans (HSPGs) from liver granulomas support myeloid cell proliferation by binding and presenting growth factors like GM-CSF and IL-3. These HSPGs are crucial for controlling inflammatory cell production in hepatic granulomas.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Connective tissue cells in liver granulomas sustain myeloid cell proliferation.
- The molecular mechanisms controlling this stroma-dependent inflammatory cell production are not fully understood.
Purpose of the Study:
- To investigate the role of heparan sulfate proteoglycans (HSPGs) in regulating myeloid cell proliferation within hepatic granulomas.
- To elucidate the molecular mechanisms by which stroma-derived HSPGs control inflammatory cell production.
Main Methods:
- Purification of HSPGs from granuloma-derived connective tissue cells.
- Assaying HSPG binding of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3).
- Monitoring stimulation of myeloid cell proliferation (FDC-P1 lineage) and modification of growth factor activity.
Main Results:
- HSPGs were required and sufficient for binding and presenting GM-CSF and IL-3 in a biologically active form.
- HSPGs increased the specific growth-promoting activity of GM-CSF and IL-3.
- This effect was specific to stroma-derived heparan sulfate and heparin, not other glycosaminoglycans.
Conclusions:
- HSPGs act as an artificial myelopoietic stroma, stimulating and controlling myeloid cell proliferation in situ.
- HSPGs modify the quantitative and qualitative composition of inflammatory cell infiltrates in hepatic granulomas.