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

Marco Mirani, Ilia Elenkov, Simona Volpi, Naoki Hiroi, George P. Chrousos, Tomoshige Kino

Research output: Contribution to journalArticle

75 Citations (Scopus)

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 KB- 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.

Original languageEnglish
Pages (from-to)6361-6368
Number of pages8
JournalJournal of Immunology
Volume169
Issue number11
Publication statusPublished - 1 Dec 2002
Externally publishedYes

Fingerprint

Interleukin-12
Innate Immunity
Cellular Immunity
Glucocorticoids
Action Potentials
HIV Infections
Glucocorticoid Receptors
HIV-1
Monocytes
Hydrocortisone
Acquired Immunodeficiency Syndrome
vpr Gene Products
Macrophages
Mifepristone
Interleukin-10
Dexamethasone
Formaldehyde
Staphylococcus aureus
Immune System
Hypersensitivity

ASJC Scopus subject areas

  • Immunology

Cite this

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. / Mirani, Marco; Elenkov, Ilia; Volpi, Simona; Hiroi, Naoki; Chrousos, George P.; Kino, Tomoshige.

In: Journal of Immunology, Vol. 169, No. 11, 01.12.2002, p. 6361-6368.

Research output: Contribution to journalArticle

@article{fb453e4928ff439095301bdddad76cf3,
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 KB- 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.",
author = "Marco Mirani and Ilia Elenkov and Simona Volpi and Naoki Hiroi and Chrousos, {George P.} and Tomoshige Kino",
year = "2002",
month = "12",
day = "1",
language = "English",
volume = "169",
pages = "6361--6368",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "11",

}

TY - JOUR

T1 - HIV-1 protein Vpr suppresses IL-12 production from human monocytes by enhancing glucocorticoid action

T2 - Potential implications of Vpr coactivator activity for the innate and cellular immunity deficits observed in HIV-1 infection

AU - Mirani, Marco

AU - Elenkov, Ilia

AU - Volpi, Simona

AU - Hiroi, Naoki

AU - Chrousos, George P.

AU - Kino, Tomoshige

PY - 2002/12/1

Y1 - 2002/12/1

N2 - 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 KB- 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.

AB - 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 KB- 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.

UR - http://www.scopus.com/inward/record.url?scp=0036885129&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036885129&partnerID=8YFLogxK

M3 - Article

C2 - 12444143

AN - SCOPUS:0036885129

VL - 169

SP - 6361

EP - 6368

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 11

ER -