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Prepublished online as a Blood First Edition Paper on September 19, 2002; DOI 10.1182/blood-2002-06-1665.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 998-1006
IMMUNOBIOLOGY
cAMP inhibits both Ras and Rap1 activation in primary human T
lymphocytes, but only Ras inhibition correlates with blockade of cell
cycle progression
Thomas Grader-Beck,
Andre A. F. L. van Puijenbroek,
Lee M. Nadler, and
Vassiliki A. Boussiotis
From the Department of Adult Oncology, Dana-Farber
Cancer Institute; Division of Medical Oncology, Brigham and Women's
Hospital; and Department of Medicine, Harvard Medical School, Boston,
MA.
Cyclic adenosine monophosphate (cAMP) is a negative
regulator of T-cell activation. However, the effects of cAMP on
signaling pathways that regulate cytokine production and cell cycle
progression remain unclear. Here, using primary human T lymphocytes in
which endogenous cAMP was increased by the use of forskolin
and 3-isobutyl-1-methylxanthine (IBMX), we show that increase
of cAMP resulted in inhibition of T-cell receptor (TCR)/CD3 plus
CD28-mediated T-cell activation and cytokine production and blockade
of cell cycle progression at the G1 phase. Increase of cAMP
inhibited Ras activation and phosphorylation of mitogen-induced
extracellular kinase (MEK) downstream targets extracellular
signal-related kinase 1/2 (ERK1/2) and phosphatidylinositol-3-kinase
(PI3K) downstream target protein kinase B (PKB; c-Akt). These
functional and biochemical events were secondary to the impaired
activation of ZAP-70 and phosphorylation of LAT and did not
occur when cells were stimulated with phorbol ester, which bypasses the
TCR proximal signaling events and activates Ras. Increase of cAMP also
inhibited activation of Rap1 mediated by TCR/CD3 plus CD28.
Importantly, inhibition of Rap1 activation by cAMP was also observed
when cells were stimulated with phorbol ester, although under these
conditions Ras was activated and cells progressed into the cell cycle.
Thus, TCR plus CD28-mediated activation of ERK1/2 and PKB, cytokine
production, and cell cycle progression, all of which are inhibited by
cAMP, require activation of Ras but not Rap1. These results indicate
that signals that regulate cAMP levels after encounter of T cells by
antigen will likely determine the functional fate toward clonal
expansion or repression of primary T-cell responses.
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