title: Interferon alpha2b directly induces fibroblast proliferation and transforming growth factor beta secretion of macrophages.
abstract: To elucidate the effects of interferon alpha2b (IFN-alpha) 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 beta1 (TGF-beta1) 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-alpha 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-beta and PDGF. In the megakaryocyte-enriched co-cultures, the fibroblast proliferation was not altered by IFN-alpha, but in the macrophage fibroblast cultures addition of IFN-alpha 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-alpha treatment exerted a significantly elevated TGF-beta1 secretion in single macrophages. Our findings are in keeping with the assumption that several pathomechanisms participate in IFN-alpha-induced myelofibrosis, including direct and indirect effects.
authors.affiliation: Institute of Pathology and 1st Clinic of Medicine, University of Cologne, 50924 Cologne, Germany. c.wickenhauser@uni-koeln.de
authors.forename: C
authors.initials: C
authors.lastname: Wickenhauser
authors.forename: B
authors.initials: B
authors.lastname: Schmitz
authors.forename: B
authors.initials: B
authors.lastname: Selbach
authors.forename: C
authors.initials: C
authors.lastname: Brockbals
authors.forename: O
authors.initials: O
authors.lastname: Manske
authors.forename: J
authors.initials: J
authors.lastname: Thiele
mesh_terms: D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000166:cytology*; D002450:Cell Communication; D002455:Cell Division / Q000276:immunology; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006462:Hemolytic Plaque Technique; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism; D008875:Middle Aged; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins; D013268:Stimulation, Chemical; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010982:Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta