title: HIV-1 protein Vpr suppresses IL-12 production from human monocytes by enhancing glucocorticoid action: potential implications of Vpr coactivator activity for the innate and cellular immunity deficits observed in HIV-1 infection.
abstract: The HIV-1 protein Vpr has glucocorticoid receptor coactivator activity, potently increasing the sensitivity of glucocorticoid target tissues to cortisol. Patients with AIDS and normal cortisol secretion have manifestations compatible with glucocorticoid hypersensitivity of the immune system, such as suppression of innate and cellular immunities. The latter can be explained by glucocorticoid-induced inhibition of cytokine networks regulating innate and Th1-driven cellular immunity. We demonstrated that extracellularly administered Vpr protein dose-dependently potentiated glucocorticoid-induced suppression of both mRNA expression and secretion of IL-12 subunit p35 and IL-12 holo-protein, but not IL-12 subunit p40 or IL-10, by human monocytes/macrophages stimulated with LPS or heat-killed, formalin-fixed Staphylococcus aureus (Cowan strain 1). This effect was inhibited by the glucocorticoid receptor antagonist RU 486. Also, Vpr changed the expression of an additional five glucocorticoid-responsive genes in the same direction as dexamethasone and was active in potentiating the trans-activation, but not the trans-repression, properties of the glucocorticoid receptor on nuclear factor kappaB- or activating protein 1-regulated simple promoters. Thus, extracellular Vpr enhances the suppressive actions of the ligand-activated glucocorticoid receptor on IL-12 secretion by human monocytes/macrophages. Through this effect, Vpr may contribute to the suppression of innate and cellular immunities of HIV-1-infected individuals and AIDS patients.
authors.affiliation: Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Mirani
authors.forename: Ilia
authors.initials: I
authors.lastname: Elenkov
authors.forename: Simona
authors.initials: S
authors.lastname: Volpi
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiroi
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
mesh_terms: D001483:Base Sequence; D004279:DNA, Viral / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D016336:Gene Products, vpr / Q000235:genetics / Q000276:immunology*; D005938:Glucocorticoids / Q000494:pharmacology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D015497:HIV-1; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D054325:vpr Gene Products, Human Immunodeficiency Virus
chemical_list: D004279:DNA, Viral; D016336:Gene Products, vpr; D005938:Glucocorticoids; D006727:Hormone Antagonists; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; D018664:Interleukin-12; D015735:Mifepristone; D003907:Dexamethasone