Administration of interleukin-6 stimulates multilineage hematopoiesis and accelerates recovery from radiation-induced hematopoietic depression

Abstract

Hematopoietic depression and subsequent susceptibility to potentially lethal opportunistic infections are well-documented phenomena following radiotherapy. Methods to therapeutically mitigate radiation-induced myelosuppression could offer great clinical value. In vivo studies in our laboratory have demonstrated that interleukin-6 (IL-6) stimulates pluripotent hematopoietic stem cell (CFU-s), granulocyte-macrophage progenitor cell (GM-CFC), and erythroid progenitor cell (CFU-e) proliferation in normal mice. Based on these results, the ability of IL- 6 to stimulate hematopoietic regeneration following radiation-induced hematopoietic injury was also evaluated. C3H/HeN female mice were exposed to 6.5 Gy 60Co radiation and subcutaneously administered either saline or IL-6 (1,000 micrograms/kg) on days 1 through 3 or 1 through 6 postexposure. On days 7, 10, 14, 17, and 22, femoral and splenic CFU-s, GM-CFC, and CFU-e contents and peripheral blood white cell, red cell, and platelet counts were determined. Compared with saline treatment, both 3-day and 6-day IL-6 treatments accelerated hematopoietic recovery; 6-day treatment produced the greater effects. For example, compared with normal control values (N), femoral and splenic CFU-s numbers in IL-6-treated mice 17 days postirradiation were 27% N and 136% N versus 2% N and 10% N in saline-treated mice. At the same time, bone marrow and splenic GM-CFC values were 58% N and 473% N versus 6% N and 196% N in saline-treated mice; bone marrow and splenic CFU-e numbers were 91% N and 250% N versus 31% N and 130% N in saline-treated mice; and peripheral blood white cell, red cell, and platelet values were 210% N, 60% N, and 24% N versus 18% N, 39% N, and 7% N in saline- treated mice. These studies demonstrate that therapeutically administered IL-6 can effectively accelerate multilineage hematopoietic recovery following radiation-induced hematopoietic injury.

The Efficacy of Recombinant Thrombopoietin in Murine and Nonhuman Primate Models for Radiation‐Induced Myelosuppression and Stem Cell Transplantation

“…Therefore, the dose schedule of 21 consecutive days of treatment was supraoptimal, as was also evident from the supranormal platelet numbers reached in the second and third week after TBI; this is consistent with the observation in a mouse model for thrombocytopenia that a single dose of TPO given 24 h after the cytoreductive therapy is as effective as daily dosing for eight consecutive days [28]. The effect of a single injection in this model was also highly dose-dependent and shows that TPO is clearly more effective in stimulating platelet recovery than other growth factors known to stimulate platelet production, such as IL-6 [29][30][31][32], IL-11 [33,34], IL-3 [31,32], and IL-1 [35]. All of these cytokines stimulate platelet production, but not all are sufficiently effective for preventing thrombocytopenia at tolerable doses in view of adverse effects.…”

Progenitor cell hyperplasia with rare development of myeloid leukemia in interleukin 11 bone marrow chimeras.

“…By comparison, short-term treatment of normal mice with IL-11 resulted in modest increases in peripheral platelet levels above those of vehicle-treated controls (*1.3-fold) with minimal effects noted on circulating neutrophil numbers (8,17,18). These findings are comparable to those obtained by in vivo administration of IL-6 (19)(20)(21), but contrast sharply with the striking changes we observed in mice chronically exposed to high plasma concentrations of IL-6 after engraftment with bone marrow cells constitutively expressing a retrovirally introduced IL-6 gene (22). The IL-6 transplant mice uniformly developed a fatal myeloproliferative syndrome characterized by neutrophil excess (up to 400 • 103 cells/mm3), microcytic anemia, thrombocytosis followed by thrombocytopenia, and marked alterations in plasma protein levels.…”

Effect of recombinant human thrombopoietin in nonhuman primates with chemotherapy‐induced thrombocytopenia

“…A number of haemopoietic factors have been shown to affect megakaryocytopoiesis and platelet production. The effects of some of the factors on chemotherapy or radiationinduced thrombocytopenia have been tested in various animal models (Patchen et al, 1991;Zeidler et al, 1992;Laterveer et al, 1993;Winton et al, 1994;Du et al, 1993;Leonard et al, 1994;Farese et al, 1994). The present data indicate that, compared with those factors, rhTPO is most effective in ameliorating thrombocytopenia associated with myelosuppression.…”