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Interleukin-1 (IL-1), a cytokine, primarily produced by monocytes, is the molecule involved in mediating many of the body's responses associated with infection and inflammation. More recently, IL-1 has been shown to sustain elevated levels of circulating granulocytes, stimulate the production of granulocyte-macrophage colony stimulating factors (CSFs) in vitro, increase plasma levels of CSF, and act synergistically with CSFs to increase the number of granulocyte-macrophage progenitors (colony-forming units) (CFU-GM) in vitro. The purpose of this study was to investigate the effect of murine IL-1 on steady-state hematopoiesis in vivo. C3H/HeJ or its normal littermate C3H/HeN male mice were administered either murine recombinant IL-1 at 45, 50, 200, 225, or 900 units (0.0125-0.25 micrograms)/animal, or 200 units (0.05 micrograms) of semipurified IL-1 derived from P388D1 cell culture supernatants. Because one of the responses to IL-1 is increased prostaglandin (PG) production and with the known activity of PGs on hematopoiesis, additional studies incorporated the cyclooxygenase inhibitor indomethacin (IM) (10 mg/kg body weight). In order to study the effect of IL-1 in vivo on pluripotential progenitors (CFU-S), IL-1 was compared with recombinant murine GM-CSF (50, 200, and 900 units; 0.0125, 0.05, and 0.25 micrograms). Control groups consisted of animals receiving either lipopolysaccharide (0.5 mg/kg body weight) or phosphate-buffered saline where appropriate. After 24 h, animals were sacrificed, and their peripheral blood indices and stem cell content of both bone marrow and spleen were evaluated for various committed hematopoietic progenitors: CFU-GM, CFU-Meg, CFU-E, BFU-E, and CFU-DG. Circulating neutrophils were increased following IL-1; however, this increase was reduced following IM. IL-1 marrow-derived CFU-GM, CFU-E, BFU-E, and CFU-Meg were below controls. In contrast, splenic CFU-GM and CFU-Meg were significantly elevated with increasing IL-1 concentrations. Erythroid progenitors were increased following low IL-1 concentrations and reduced in animals receiving IM, thus indicating a role for prostaglandins in the mechanism of IL-1 for influencing hematopoiesis. CFU-DG were increased, however, only when animals were pretreated with IL-1 and their cells implanted into normal hosts, not when normal cells were implanted into animals pretreated with IL-1, indicating a potential target cell effect rather than an indirect, factor-related response.(ABSTRACT TRUNCATED AT 400 WORDS)

Radiation exposure to various systems can result in the development of severe toxicity, known as the acute radiation syndrome, with hematopoietic tissues being acutely susceptible to radiation-induced injury. Usually it is the degree of hematopoietic toxicity that determines the feasibility of further tumor control doses of therapy. Therefore the development of agents capable of protecting hematopoietic tissues could have important clinical applications. The cytokine interleukin-1 (IL-1) has been demonstrated to be an effective agent capable of protecting hematopoietic tissues in vivo from the toxicity associated with radiation exposure. We report here the results of studies designed to further investigate the capability of various cytokines (IL-1 and interleukins-2 and -3) to protect bone marrow-derived hematopoietic progenitors [granulocyte-macrophage and megakaryocyte colony-forming units (CFU-GM and CFU-Meg)] from radiation exposure in vitro. Only IL-1 was effective in protecting CFU-GM and CFU-Meg from radiation-induced toxicity in the range of 1-10 U/ml; however, no protection was observed when the radiation dose was greater than 300 rad. The ability of IL-1 to block radiation-induced toxicity was negated in the presence of an antibody to IL-1. These studies provide further information on the effectiveness of IL-1 in protecting in vitro hematopoietic tissues from toxicity associated with radiation exposure.