Selective inhibition of NF-kB activation and TNF-alpha production in macrophages by red blood cell-mediated delivery of dexamethasone.
Glucocorticoids 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-alpha 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 IkBalpha gene transcription and, as a consequence, by an increased rate of IkBalpha protein synthesis. Furthermore, NF-kB inactivation correlated with downmodulation of TNF-alpha mRNA expression, demonstrating that suppression of TNF-alpha production in dexamethasone-targeted cells occurs at the transcriptional level.
Crinelli
R
R
Istituto di Chimica Biologica "G. Fornaini,", Università degli Studi di Urbino, Urbino, Italy.
Antonelli
A
A
Bianchi
M
M
Gentilini
L
L
Scaramucci
S
S
Magnani
M
M
D002214:Capsules; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology*; D004337:Drug Carriers; D004912:Erythrocytes / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D002214:Capsules; D004337:Drug Carriers; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C004180:dexamethasone 21-phosphate; D003907:Dexamethasone