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Tumor Necrosis Factor Decreases, and Interleukin-10 Increases, the Sensitivity of Human Monocytes to Dexamethasone: Potential Regulation of the Glucocorticoid Receptor

Laboratory of Radio-Immunology and Neuroendocrine-Immunology (D.F., H.M., M.-T.H., W.D., V.G.), Institute of Pathology, Department of Gastroenterology CHU (D.F., E.L., J.B.), University of Liège, Belgium; and Developmental Endocrinology Branch (D.F., G.P.C.), NICHD, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Denis Franchimont, M.D., Developmental Endocrinology Branch, NICHD, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, Bethesda, Maryland 20892.

Resistance to glucocorticoid therapy has been observed in patients with autoimmune/inflammatory diseases and may be related to the inflammatory process itself. The aim of this study was to examine the ability of tumor necrosis factor (TNF, a proinflammatory cytokine) and interleukin (IL)-10 (an anti-inflammatory cytokine) to differentially regulate the sensitivity of human monocytes/macrophages to glucocorticoids. To accomplish this, we first analyzed the pattern of TNF and IL-10 inhibition by dexamethasone in LPS-stimulated whole-blood cell cultures. Second, we studied the modulation of the sensitivity of these cells to dexamethasone by preincubation with TNF or IL-10 and measurement of LPS-stimulated IL-6 secretion. In addition, we evaluated the effect of dexamethasone on phorbol-myristate-acetate-stimulated IL-1 receptor antagonist secretion by the human monocytic cell line U937. Finally, we investigated whether the modulation of corticosensitivity in TNF- and IL-10-pretreated U937 cells was related to a change of the glucocorticoid receptor concentration and affinity. Dexamethasone had different effects on LPS-induced TNF and IL-10 secretion; whereas it suppressed TNF in a dose-dependent fashion, its effect on IL-10 secretion was biphasic, producing stimulation at lower, and inhibition at higher doses. The concentration of LPS employed influenced the effect of dexamethasone on IL-10 secretion (P < 0.001). Pretreatment with TNF diminished, and with IL-10 improved, the ability of dexamethasone to suppress IL-6 secretion in whole-blood cell cultures (P < 0.01 for both) and to enhance IL-1 receptor antagonist secretion by U937 cells (P < 0.05 for both). TNF decreased (P < 0.001), while IL-10 increased (P < 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity. We conclude that glucocorticoids differentially modulate TNF and IL-10 secretion by human monocytes in a LPS dose-dependent fashion and that the sensitivity of these cells to glucocorticoids is altered by TNF or IL-10 pretreatment; TNF blocks their effects, whereas IL-10 acts synergistically with glucocorticoids. This is accompanied by opposite glucocorticoid receptor changes, respectively opposing and favoring glucocorticoid actions. This study suggests that the pattern of pro-/antiinflammatory cytokine secretion may alter the response of patients to glucocorticoid therapy.

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