Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: Potential regulation of theglucocorticoid receptor

Resistance to glucocorticoid therapy has been observed in patients with aut oimmune/inflammatory diseases and may be related to the inflammatory proces s itself. The aim of this study was to examine the ability of tumor necrosi s factor alpha (TNF alpha, a proinflammatory cytokine) and interleukin (IL) -10 (an anti-inflammatory cytokine) to differentially regulate the sensitiv ity of human monocytes/macrophages to glucocorticoids. To accomplish this, we first analyzed the pattern of TNF alpha and IL-10 inhibition by dexameth asone in LPS-stimulated whole-blood cell cultures. Second, we studied the m odulation of the sensitivity of these cells to dexamethasone by preincubati on with TNF alpha or IL-10 and measurement of LPS-stimulated IL-6 secretion . In addition, we evaluated the effect of dexamethasone on phorbol-myristat e-acetate-stimulated IL-1 receptor antagonist secretion by the human monocy tic cell line U937. Finally, we investigated whether the modulation of cort icosensitivity in TNF alpha- and IL-10-pretreated U937 cells was related to a change of the glucocorticoid receptor concentration and affinity. Dexame thasone had different effects on LPS-induced TNF alpha and IL-10 secretion; whereas it suppressed TNF alpha in a dose-dependent fashion, its effect on IL-10 secretion was biphasic, producing stimulation at lower, and inhibiti on at higher doses. The concentration of LPS employed influenced the effect of dexamethasone on IL-10 secretion (P < 0.001). Pretreatment with TNF alp ha diminished, and with IL-10 improved, the ability of dexamethasone to sup press IL-6 secretion in whole-blood cell cultures (P < 0.01 for both) and t o enhance IL-1 receptor antagonist secretion by U937 cells (P < 0.05 for bo th). TNF alpha decreased (P < 0.001), while IL-10 increased (P < 0.001), th e concentration of dexamethasone binding sites in these cells, with no disc ernible effect on their binding affinity. We conclude that glucocorticoids differentially modulate TNF alpha and IL-10 secretion by human monocytes in a LPS dose-dependent fashion and that the sensitivity of these cells to gl ucocorticoids is altered by TNF alpha or IL-10 pretreatment; TNF alpha bloc ks their effects, whereas IL-10 acts synergistically with glucocorticoids. This is accompanied by opposite glucocorticoid receptor changes, respective ly opposing and favoring glucocorticoid actions. This study suggests that t he pattern of pro-/antiinflammatory cytokine secretion may alter the respon se of patients to glucocorticoid therapy.