Influence of cytokines (IL‐1α, IL‐3, IL‐11, GM‐CSF) on megakaryocyte‐fibroblast interactions in normal human bone marrow

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Abstract
The evolution of myelofibrosis accompanying chronic myeloproliferative disorders (CMPDs) is often linked with megakaryopoiesis. However, it is not known whether or to what extent megakaryocytes of normal human bone marrow are capable of stimulating fibroblast growth. For this reason, an in vitro study was performed to elucidate possible cytokine-dependent interactions between megakaryocytes and fibroblasts derived from healthy volunteers. Fibroblast growth was significantly promoted by the presence of megakaryocytes and modulated by additional application of various cytokines. While recombinant human (rh) interleukin (IL)-1 alpha had no obvious effect on fibroblast proliferation, a slight increase was detected on adding granulocyte-macrophage colony stimulating factor (rhGM-CSF). Application of rhIL-3 caused a significant increase in the number of fibroblasts. In contrast, administration of rhIL-11 suppressed the megakaryocyte-dependent growth-promoting effect and co-stimulation with rhIL-3 led to a significant decrease of fibroblast number in comparison to rhIL-3-stimulated co-cultures. Inhibition of cell-cell contact in unstimulated, as well as in rhIL-3-stimulated co-cultured led to a conspicuous impairment of fibroblast growth. A similar effect was observed when neutralizing antibodies directed against platelet-derived growth factor (PDGF) and transforming growth factor (TGF)beta 1 were added to rhIL-3-stimulated cultures. Our findings are in keeping with the assumption that interactions between megakaryocytes and fibroblasts involve in cytokine-mediated functional network regulated by factors such as spatial relationship, cytokine stimulation, and low concentrations of mediators, particularly PDGF and TGF beta. In this complex system rhIL-3 seems to play a crucial role in the promotion of these various interrelationships.