Interferon α2b directly induces fibroblast proliferation and transforming growth factor β secretion of macrophages

Abstract

To elucidate the effects of interferon α2b (IFN-α) on normal human bone marrow, fibroblasts from patients without haematopoietic pathology were cultivated and used in stimulation experiments. Further, co-cultures with highly enriched fractions of megakaryocytes and bone marrow macrophages were analysed. In this context, the influence of cell-to-cell interactions and humoral factors was determined in transwell and neutralization studies. Finally, secretion of platelet-derived growth factor (PDGF) and transforming growth factor β1 (TGF-β1) by single megakaryocytes and macrophages was examined by using the reverse haemolytic plaque assay (RHPA). Following these experimental designs, a direct proliferative activity of IFN-α on bone marrow fibroblasts could be demonstrated. In the unstimulated co-cultures, the megakaryocyte- but not the macrophage-enriched fraction induced fibroblast growth and [3H]-thymidine uptake. This effect was dependent on cell-to-cell contact and also on the influence of TGF-β and PDGF. In the megakaryocyte-enriched co-cultures, the fibroblast proliferation was not altered by IFN-α, but in the macrophage fibroblast cultures addition of IFN- α enhanced fibroblast growth and [3H]-thymidine uptake was distinctively higher than in the monocultures. This effect was not obvious in the transwell or neutralization experiments. Finally, IFN-α treatment exerted a significantly elevated TGF-β1 secretion in single macrophages. Our findings are in keeping with the assumption that several pathomechanisms participate in IFN-α-induced myelofibrosis, including direct and indirect effects.