Polycythemia vera megakaryocytes but not megakaryocytes from normal controls and patients with smokers polyglobuly spontaneously express IL-6 and IL-6R and secrete IL-6.

Polycythemia rubra vera (PV) represents a clonal hematological disorder defined by an abnormal expansion of erythroid precursors and megakaryopoiesis, in particular. Ample evidence has been provided that the IL-6/1L-6R complex may be responsible for the proliferation of normal and neoplastic megakaryocytes in vitro and this fact lead us to the hypothesis, that defects in the regulation of IL-6 synthesis take part in the pathogenesis of PV. The study was carried out to determine the IL-6 serum levels and the megakaryocytic IL-6 production in patients with PV and to compare these data with the situation in hematologically healthy donors as well as in patients suffering from spurious polycythemia--smokers polyglobuly (PG). For this purpose, IL-6 serum levels were measured by ELISA and the megakaryocytic production studied by immunohistochemistry, reverse hemolytic plaque assay (RHPA) together with reverse transcription/polymerase chain reaction (RT-PCR) in highly enriched megakaryocyte preparations. In additional experiments, the influence of IL-3 stimulation and the expression of IL-6R were tested. Serum levels of IL-6 did not differ between the three groups under study. In contrast, immunohistochemistry revealed a raised proportion of megakaryocytes expressing IL-6 in PV as compared to normal donors and patients suffering from PG. The percentage of megakaryocytes actively secreting this cytokine as detected by the RHPA was 20 times greater than in both the other groups. This phenomenon was further substantiated by the fact that IL-6 mRNA could only be shown in PV megakaryocyte preparations. The regulation of IL-6 secretion appears to be abnormal in PV. Whereas in the normal and in the PG group IL-3 stimulation exerts a marked increase in megakaryocytic IL-6 secretion, PV megakaryocytes responded with a paradoxical down-regulation of IL-6 synthesis combined with the loss of IL-6R. Our data describe for the first time an abnormally raised IL-6 production by PV megakaryocytes and point towards fundamental regulatory alterations of the IL-6 synthesis in this disease.