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Tumor Necrosis Factor Inhibits Insulin-Like Growth Factor I-Induced Hematopoietic Cell Survival and Proliferation

Laboratory of Immunophysiology (W.H.S., J.H.Z., S.R.B., K.W.K.) and Laboratory of Integrative Biology (R.W.J.), Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801; and Integrative Neurobiology, French Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Bordeaux 2, Institut François Magendie des Neurosciences (R.D), 33077 Bordeaux Cedex, France

Address all correspondence and requests for reprints to: Dr. Keith W. Kelley, University of Illinois, Laboratory of Immunophysiology, Department of Animal Sciences, 207 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, Illinois 61801. E-mail: kwkelley{at}uiuc.edu.

Abstract

Proinflammatory cytokines, such as TNF and IL-1ß, are both cytostatic and cytotoxic. In contrast, IGF-I promotes proliferation and survival of hematopoietic progenitor cells. In this report, we establish that both the cytostatic and cytotoxic activity of TNF on murine myeloid progenitor cells is only evident in the presence of IGF-I. We first confirmed that IGF-I (100 ng/ml) increases DNA synthesis and reduces apoptosis in murine myeloid progenitor cells induced to die by growth factor withdrawal. TNF inhibits, in a dose-dependent fashion from 0.1 to 10 ng/ml, both activities of IGF-I. TNF activity was not detected in the absence of IGF-I. Another proinflammatory cytokine, IL-1ß, did not inhibit IGF-I-induced activity in murine factor-dependent cell progenitor-1/Mac-1 cells. However, the ability of TNF to impair IGF-I-induced DNA synthesis in human promyeloid cells extends to IL-1ß. Statistically significant inhibition of all these events occurs at very low concentrations of 1 ng/ml or less. These results support the general concept that proinflammatory cytokines impair the actions of hormones on hematopoietic cells, leading to IGF-I receptor resistance.

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