Selective Inhibition of NF-kB Activation and TNF-α Production in Macrophages by Red Blood Cell-Mediated Delivery of Dexamethasone

Abstract

ABSTRACTGlucocorticoids are a widely used class of anti-inflammatory and immunosuppressive drugs, but their therapeutic use is limited by endocrine and metabolic side effects that they produce when given systemically. Since cells of the monocyte/macrophage lineage play an important role in the pathogenesis of several autoimmune and inflammatory diseases, a drug-delivery system which targets phagocytic cells was studied. We had previously demonstrated that dexamethasone, a potent glucocorticoid analogue, can be encapsulated in erythrocytes and selectively delivered to macrophages. In addition, lipopolysaccharide (LPS) stimulation of dexamethasone-targeted macrophages results in the suppression of TNF-α secretion. In this paper we demonstrate that the administration of dexamethasone to macrophages by means of opsonized red blood cells allows efficient interference with NF-kB activation. This NF-kB repression was in part mediated by induction of IkBα gene transcription and, as a consequence, by an increased rate of IkBα protein synthesis. Furthermore, NF-kB inactivation correlated with downmodulation of TNF-α mRNA expression, demonstrating that suppression of TNF-α production in dexamethasone-targeted cells occurs at the transcriptional level.