INTERLEUKIN-10 INHIBITS ERYTHROPOIETIN-INDEPENDENT GROWTH OF ERYTHROID BURSTS IN PATIENTS WITH POLYCYTHEMIA-VERA

In polycythemia vera (PV) erythroid colonies that grow in vitro in the absence of exogenous erythropoietin (EPO) arise from the abnormal clo ne that is responsible for overproduction of red blood cells. Although the mechanism of autonomous formation of burst-forming units-erythroi d (BFU-E) is not fully understood, a spontaneous release of growth reg ulatory molecules by PV cells and/or by accessory cells is likely to b e involved. Because of its cytokine synthesis inhibiting action, inter leukin-10 (IL-10) could be a potentially useful molecule to modulate a bnormal erythropoiesis in PV. We studied the effect of recombinant hum an IL-10 on the EPO-independent growth of erythroid bursts derived fro m peripheral blood mononuclear cells (PBMNCs) of patients with PV. IL- 10 showed a profound, dose-dependent, and specific inhibitory effect o n autonomous BFU-E formation. Ten nanograms per milliliter of IL-10 si gnificantly suppressed spontaneous growth of erythroid colonies in met hylcellulose in five of five PV patients tested with a mean inhibition by 81% (range, 72-94). To elucidate the possible mechanism of the inh ibitory action of IL-10 we further studied the effect of anticytokine antibodies on autonomous BFU-E growth and the ability of exogenous cyt okines to restore IL-10-induced suppression of erythroid colony growth . Among a panel of growth regulatory factors tested (granulocyte-macro phage colony-stimulating factor [GM-CSF], IL-3, granulocyte colony-sti mulating factor, stem cell factor, and insulin-like growth factor-1) G M-CSF was the only molecule for which both an inhibition of spontaneou s BFU-E formation by its respective antibody as well as a significant restimulation of erythroid colonies in IL-10-treated cultures by exoge nous addition was found. Moreover, inhibition of GM-CSF production by IL-10 was shown in PV PBMNCs at the mRNA level. Our data indicate that autonomous BFU-E growth in PV can be profoundly inhibited by IL-10 an d that this inhibitory effect seems to be at least in part secondary t o suppression of endogenous GM-CSF production. (C) 1998 by The America n Society of Hematology.