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Glucocorticoids Inhibit Lipopolysaccharide-Induced Production of Tumor Necrosis Factor- by Human Fetal Kupffer Cells^*

Division of Reproductive Endocrinology and the Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center Dallas, Texas 75235

Address requests for reprints to: William H. Kutteh, M.D., Ph.D., Department of Obstetrics and Gynecology-J6.114, 5323 Harry Hines Boulevard, University of Texas Southwestern Medical Center, Dallas, Texas 75235–9032.

Inflammatory mediators, such as interleukin-1β (IL-1β) and tumor necrosis factor- (TNF) are secreted by fixed tissue macrophages and exhibit local autocrine and paracrine effects as well as distant endocrine effects. Human fetal Kupffer cells, the fixed tissue macrophages of the liver, may play a role as modulators of immune and endocrine function in early embryonic and fetal development. In the present study we isolated human fetal Kupffer cells to greater than 90% purity and prepared short term cultures to investigate the effect of glucocorticoids on the secretion of the cytokine TNF. Fetal Kupffer cells secreted TNF and IL-1β after culture with bacterial lipopolysaccharide (LPS), indicating that these cells express mature macrophage function. Cortisol and dexamethasone dramatically suppressed the LPS-stimulated secretion of TNF by fetal Kupffer cells. The inhibitory effects of glucocorticoids appeared to be specific, since estrogen, progesterone, and testosterone had no effect on LPS stimulation of TNF production. None of the steroids tested altered basal production or enhanced the LPS-stimulated production of TNF by fetal Kupffer cells. The inhibition by glucocorticoids could be reversed by the addition of RU 486, indicating that this effect was mediated by the glucocorticoid receptor. These results demonstrate that human fetal macrophages demonstrate mature macrophage function in early gestation; they can be activated to produce TNF by a well characterized modulator of cellular function (LPS) and suppressed by glucocorticoids.

^* This work was supported by NIH Research Grants HD-07190 and HD-1784. WHK is the recipient of the AFS/Ortho Distinguished Fellowship in Reproduction.

Received August 31, 1990.

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