The erythropoietic effects of interleukin 6 and erythropoietin in vivo.

The purpose of this investigation was to compare the erythropoietic effects of recombinant interleukin 6 (IL-6) and recombinant erythropoietin (EPO) on the marrow and peripheral blood in vivo. IL-6 administered to rats as a single i.v. injection induces a selective erythroid hyperplasia of the marrow's late normoblasts at 12 and 24 h with a return to preinjection numbers of normoblasts at 48 and 72 h. The hyperplasia of late normoblasts in the marrow is accompanied by a left-shifted peripheral reticulocytosis. Daily injection of IL-6 does not induce any effects on the erythroid population of the marrow or circulation beyond those of a single injection. After daily administration of IL-6 for 4 or 7 days, the erythroid differential in the marrow and the peripheral reticulocyte count are equal to negative control values, indicating a rapid tachyphylaxis to the erythropoietic effect of IL-6. In contrast to IL-6, EPO administered as a single i.v. injection induces a panerythroid marrow hyperplasia with sequential peak increases in pronormoblasts and early normoblasts at 24 h, intermediate normoblasts at 24-48 h, and late normoblasts at 72 h. The peripheral reticulocyte count mirrors the development of erythroid precursors in the marrow by demonstrating an increasing left-shifted reticulocytosis between 24 and 72 h. Daily injection of EPO for 7 days induces a striking erythroid hyperplasia and a myeloid hypoplasia in the marrow. In summary, IL-6 in vivo is a differentiation factor that rapidly induces tolerance to its own effect, whereas EPO in vivo affects all stages of erythropoiesis and sustains erythropoiesis indefinitely. IL-6 may be one of the non-EPO factors in pokeweed mitogen spleen cell-conditioned medium that has been reported by previous investigators to enhance erythropoiesis, although many of those factors were thought to act upon an earlier stage of erythropoiesis. IL-6 is unlikely to exert an indirect erythropoietic effect in vivo via the induction of EPO because the sera of IL-6-treated rats did not contain elevated levels of EPO and because the effects of exogenously administered IL-6 and EPO are so different.