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Effects of Myelotoxic Agents on Cytokine Production in Murine Long-Term Bone Marrow Cultures

Departments of Medicine, Physiology, and Biophysics, University of Arkansas for Medical Sciences, and Geriatric Research, Education and Clinical Center (GRECC), John L. McClellan Memorial Veterans Administration Hospital, Little Rock, Arkansas, USA

Key Words. Bone marrow culture • Stroma • Interleukin 6 • M-CSF • Methotrexate • Ceftazidime

Dr. Simon P. Hauser, Central Hematology Laboratory, Inselspital, University Hospital Bern, CH-3010 Bern, Switzerland.

In long-term bone marrow cultures we studied the effect of the addition of the myelotoxic agents methotrexate (MTX) and ceftazidime (CEF) on the kinetics of cytokine production in the supernatant (SN) and on mRNA expression in the adherent stromal layer. In response to a medium change, a prompt and significant increase in colony-stimulating activity (CSA) and interleukin 6 (IL-6) concentrations in the SN occurred, peaking 12 h later. Two macrophage colony-stimulating factors (M-CSF) mRNA of 2.3 kb and 4 kb were identified. In response to the medium change, the 4.0-kb transcript increased significantly six h later. The 2.3-kb transcript expression was stronger than the 4-kb mRNA but did not cycle with medium change. At medium change, IL-6 mRNA was only minimally expressed; then a prompt increase occurred, which peaked six h later. The addition of 500 mg/ml (=915 µM) CEF to the culture caused a dose-dependent suppression of CSA and IL-6 supernatant concentrations and IL-6 and M-CSF mRNA expression. By contrast, 1 µM MTX had minimal effect on cytokine concentrations in the SN following medium change. mRNA expression was, however, suppressed. These results provide insights into the possible mechanisms whereby cytokines lead to increased myeloid cell proliferation following medium change. We also demonstrate that two myelotoxic agents have different effects on cytokine production. This information could be of value in developing rational approaches to the therapeutic use of cytokines in drug-induced neutropenia.

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