J Virol, June 1998, p. 4712-4720, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
B and NFAT
Department of Immunology,
Received 11 August 1997/Accepted 20 February 1998
Rolipram, a phosphosdiesterase type IV-specific inhibitor,
prevented p24 antigen release from anti-CD3-activated human
immunodeficiency virus (HIV)-infected T cells and CD4+-cell
depletion associated with viral replication in a dose-responsive manner
but minimally inhibited T-cell proliferation. Moreover, rolipram
reduced the production of tumor necrosis factor alpha (TNF-
) and
interleukin-10 (IL-10) by HIV-infected T cells. The transcriptional
ability of a luciferase reporter gene under control of the HIV long
terminal repeat, induced by phorbol myristic acetate plus ionomycin or
by TNF-
, in primary T and Jurkat cells was also inhibited by
rolipram. Rolipram inhibited NF-
B and NFAT activation induced by
T-cell activation in Jurkat and primary T cells, as measured by
transient transfection of reporter genes and electrophoretic mobility
shift assays. Exogenous addition of TNF-
in the presence of rolipram
restored NF-
B but not NFAT activation or p24 release. Addition of
dibutyryl-cyclic AMP (dBcAMP) mimicked the effects of rolipram on p24
antigen release, NF-
B activation, and TNF-
secretion, but it did
not affect NFAT activation or IL-10 production. The protein kinase A
inhibitor KT5720 prevented the inhibition of TNF-
secretion but not
that of HIV type 1 (HIV-1) replication caused by rolipram. Our data
indicate that blockade of phosphodiesterase type IV could be of benefit
against HIV-1 disease by modulating cytokine secretion and
transcriptional regulation of HIV replication, and they suggest an
important role of NFAT in HIV replication in primary T cells. Some of
those activities cannot be ascribed solely to its ability to increase
cAMP.
*
Corresponding author. Mailing address: Hospital General
Universitario Gregorio Marañon, Servicio de Inmunologia, c/Dr.
Esquerdo 47, 28007 Madrid, Spain. Phone: 34-1-5868565. Fax:
34-1-5868018. E-mail: Mmunoz{at}trasto.cbm.uam.es.
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