Recombinant human interleukin-1 receptor antagonist protects early myeloid progenitors in a murine model of cyclophosphamide-induced myelotoxicity.

Expression of hematoregulatory cytokines such as interleukin-1 (IL-1) in response to cytotoxic chemotherapy hastens hematopoietic recovery, but may also potentiate myelotoxicity if myeloid progenitors enter cell cycle before drug clearance. In the present study, the ability of recombinant human IL-1 receptor antagonist (IL-1ra) to protect hematopoietic progenitors was studied in a murine model of cyclophosphamide (CPA)-induced myelotoxicity. CF-1 female mice received 200 mg/kg CPA and either 10 mg/kg IL-1ra or an equal volume of 0.05% human serum albumin (HSA) intraperitoneally (i.p.), followed 12 hours later by IL-1ra or HSA. CPA and IL-1ra increased absolute neutrophil counts (ANCs) at days 2 (P = .001) and 14 (P = .0025) after CPA. In IL-1ra-treated mice, colony-forming units granulocyte-macrophage (CFU-GM)/tibia were increased twofold and threefold at days 2 (P = .0047) and 7 (P = .023), respectively, whereas high proliferative potential colony-forming cells (HPP-CFC)/tibia were decreased twofold to threefold at 8 hours (P = .039) and 24 hours (P = .0033), but were approximately threefold higher than HSA-treated mice at day 7 after CPA. Coadministration of CPA and IL-1 enhanced myelotoxicity compared with mice injected with CPA and IL-1ra or HSA. In vivo, IL-1ra protected HPP-CFC, but not CFU-GM, from hydroxyurea suicide after a single dose of CPA, suggesting that IL-1ra inhibited cycling of HPP-CFC. In vitro, IL-1ra did not alter proliferation of CFU-GM, but inhibited IL-1-enhanced proliferation of HPP-CFC. These data suggest that IL-1ra acts as an indirect negative regulator of hematopoiesis and protects HPP-CFC from CPA, possibly by inhibiting IL-1-enhanced proliferation of early myeloid progenitors.

The myelopoietic effects of a Serratia marcescens-derived biologic response modifier in a mouse model of thermal injury.

The proliferative defects observed in phagocytic stem cells after major thermal injuries may be caused by an inadequate production of colony-stimulating factors (CSFs), a family of hemopoietic cytokines necessary for the production and function of granulocytes and monocytes. In this study a biologic response modifier (S-BRM) consisting of sized vesicles derived from the cell membrane and ribosomes of Serratia marcescens was investigated in a mouse model of thermal injury to determine its ability to augment postburn myelopoiesis. Treatment of burned mice with S-BRM was well tolerated and was associated with statistically significant increases in absolute numbers of circulating granulocytes and monocytes compared with burned mice receiving saline solution. In addition, the size of the splenic myeloid stem cell compartment, as measured by granulocyte-macrophage stem cell colony formation in soft agar, was markedly expanded. Finally, plasma levels of CSF were increased significantly in burned mice receiving S-BRM but were not elevated in burned littermates treated with saline solution. These data suggest that production of CSF is suboptimal after thermal injury and S-BRM is capable of up-regulating postburn myelopoiesis by causing the release of CSF into the systemic circulation.

Interleukin-1 enhances murine granulopoiesis in vivo.

Interleukin-1 (IL-1), a monokine involved in host response to infection and inflammation, has recently been shown to stimulate production of granulocyte-monocyte colony-stimulating factors (CSFs) from a variety of cell types in vitro. The purpose of this study was to investigate the effects of human IL-1 on granulopoiesis in vivo. CF1 female mice were injected with a single dose of either highly purified human IL-1 or recombinant human IL-1 alpha (rIL-1 alpha). Heat-inactivated IL-1 or rIL-1 alpha served as controls. Physiologic doses of the IL-1 preparations were initially established by evaluating neutrophil egress from bone marrow (BM). Significant peripheral neutrophilia developed 3 h after injection of 10 U (doubling units) purified IL-1, in association with decreased marrow neutrophils. Significant neutrophilia occurred 6 h after injection of 5 x 10(3) U (half-maximal units) rIL-1 alpha. Serum colony-stimulating activity (CSA) and BM colony formation (CFU-GM) were subsequently measured in standard agar culture at various times following injection. A significant rise in CSA occurred between 3 and 6 h after injection of purified IL-1, and a significant increase in BM CFU-GM developed 48 h after injection. Similar increases in CSA and CFU-GM occurred following injection of rIL-1 alpha. These results suggest that IL-1 may play an important role in the regulation of granulopoiesis in vivo by enhancing the production of CSFs required for myeloid proliferation.