PMID- 11713366
OWN - NLM
STAT- MEDLINE
DCOM- 20020131
LR  - 20180821
IS  - 1076-1551 (Print)
IS  - 1528-3658 (Electronic)
IS  - 1076-1551 (Linking)
VI  - 7
IP  - 10
DP  - 2001 Oct
TI  - Interleukin-6 and glucocorticoids synergistically induce human immunodeficiency 
      virus type-1 expression in chronically infected U1 cells by a long terminal 
      repeat independent post-transcriptional mechanism.
PG  - 668-78
AB  - BACKGROUND: Glucocorticoids (GC) such as dexamethasone (Dex) can directly 
      upregulate human immunodeficiency virus type-1 (HIV-1) replication in acutely 
      infected cells and potentiate HIV expression from chronically infected 
      promonocytic U1 cells stimulated with tumor necrosis factor-alpha (TNF-alpha). We 
      have here investigated the potential effect of Dex in U1 cells stimulated with 
      interleukin-6 (IL-6), a cytokine inducing virus expression by acting mostly at a 
      post-transcriptional level on the virus life cycle. MATERIALS AND METHODS: Virus 
      production in culture supernatants was evaluated by reverse transcriptase (RT) 
      activity. GC receptor expression was tested by both binding of [3H]-Dexamethasone 
      21-mesylate and Northern blotting. Cell-associated HIV protein expression was 
      analyzed by Western blotting, whereas both HIV and monocyte chemoattractant 
      protein-1 (MCP-1) RNA accumulation were evaluated by Northern blotting. HIV 
      transcription was tested by long terminal repeat (LTR) chloramphenicol acetyl 
      transferase (CAT) assay after transient transfection of U1 or U937 cells. 
      Formation of activating protein-1 (AP-1) DNA binding complex in nuclear cell 
      extracts was visualized by electrophoretic mobility shift assay (EMSA), whereas 
      ERK1/2 mitogen-activated protein kinase (MAPK) phosphorylation was studied by 
      Western blotting. RESULTS: IL-6 and Dex synergistically induced HIV expression in 
      U1 cells, and this effect was blocked by RU 486. No substantial HIV RNA 
      accumulation was demonstrated in U1 cells co-stimulated with IL-6 and Dex, 
      whereas IL-6 upregulated the expression of MCP-1 RNA, and this effect was 
      inhibited by Dex. In contrast, Dex potentiated IL-6 induced activation of AP-1 
      and ERK1/2 MAPK phosphorylation, as revealed by EMSA. HIV-1 LTR driven 
      transcription was observed in U1 cells stimulated with TNF-alpha and this effect 
      was potentiated by Dex. In sharp contrast, no induction of LTR-directed CAT 
      activity was observed in transfected U1 cells (or in their parental uninfected 
      U937 cells) stimulated with IL-6 and Dex either alone or in combination. 
      CONCLUSIONS: High levels of virion production can be induced in latently infected 
      cells by stimulation with IL-6 and Dex in the absence of activation of the HIV 
      LTR or viral transcription in spite of activation of both ERK1/2 MAPK and AP-1. 
      These findings suggest the existence of LTR-independent pathways influenced by 
      cytokine and GC through which HIV can maintain substantial levels of protein 
      expression and virion production.
FAU - Kinter, A L
AU  - Kinter AL
AD  - Laboratory of Immunoregulation, National Institute of Allergy and Infectious 
      Diseases, National Institutes of Health, Bethesda, MD, USA.
FAU - Biswas, P
AU  - Biswas P
FAU - Alfano, M
AU  - Alfano M
FAU - Justement, J S
AU  - Justement JS
FAU - Mantelli, B
AU  - Mantelli B
FAU - Rizzi, C
AU  - Rizzi C
FAU - Gatti, A R
AU  - Gatti AR
FAU - Vicenzi, E
AU  - Vicenzi E
FAU - Bressler, P
AU  - Bressler P
FAU - Poli, G
AU  - Poli G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Mol Med
JT  - Molecular medicine (Cambridge, Mass.)
JID - 9501023
RN  - 0 (Autoantigens)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Glucocorticoids)
RN  - 0 (Interleukin-6)
RN  - 0 (RNA, Viral)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (Transcription Factor AP-1)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - EC 2.3.1.28 (Chloramphenicol O-Acetyltransferase)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - O9S11FMA79 (dexamethasone 21-methanesulfonate)
SB  - IM
MH  - Autoantigens/genetics/metabolism
MH  - Blotting, Northern
MH  - Blotting, Western
MH  - *Chemokine CCL2
MH  - Chloramphenicol O-Acetyltransferase/metabolism
MH  - Dexamethasone/*analogs & derivatives/*pharmacology
MH  - Drug Synergism
MH  - Electrophoretic Mobility Shift Assay
MH  - Glucocorticoids/*pharmacology
MH  - HIV Long Terminal Repeat/drug effects/physiology
MH  - HIV-1/*physiology
MH  - Humans
MH  - Interleukin-6/*pharmacology
MH  - Mitogen-Activated Protein Kinase Kinases/physiology
MH  - Monocytes/*drug effects/virology
MH  - RNA, Viral/biosynthesis
MH  - Receptors, Glucocorticoid/metabolism
MH  - Signal Transduction
MH  - Transcription Factor AP-1/metabolism
MH  - Virus Activation/drug effects
MH  - Virus Replication/drug effects
PMC - PMC1949996
EDAT- 2001/11/20 10:00
MHDA- 2002/02/01 10:01
PMCR- 2001/10/01
CRDT- 2001/11/20 10:00
PHST- 2001/11/20 10:00 [pubmed]
PHST- 2002/02/01 10:01 [medline]
PHST- 2001/11/20 10:00 [entrez]
PHST- 2001/10/01 00:00 [pmc-release]
AID - S1528365801006681 [pii]
PST - ppublish
SO  - Mol Med. 2001 Oct;7(10):668-78.