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Production by Rolipram1
*
Portland Veterans Affairs Medical Center, and
Department of Medicine, Oregon Health Sciences University, Portland, OR 97201
Agents that increase intracellular cAMP have been shown to reduce
joint inflammation in experimental arthritis, presumably by lowering
the release of proinflammatory cytokines, such as TNF-
. Recent
studies suggest that, in joints of patients with rheumatoid arthritis,
TNF- release from macrophages is triggered by their interaction with
IL-15-stimulated T lymphocytes. In this report, we analyze the effect
of rolipram, a cAMP-specific phosphodiesterase inhibitor, on TNF-
production in this experimental system. Cocultures of U937 cells with
IL-15-stimulated T cells, but not control T cells, resulted in
increased release of TNF-. Pretreatment of T cells with rolipram or
cAMP analogues inhibited the IL-15-stimulated increases in
proliferation, expression of cell surface molecules CD69, ICAM-1, and
LFA-1, and release of TNF- from macrophages. Addition of PMA to T
cells dramatically increased the expression of cell surface molecules,
but had little or no effect on TNF- release from either T cells or
from cocultures, suggesting that other surface molecules must also be
involved in T cell/macrophage contact-mediated production of TNF-.
Addition of PMA synergistically increased the proliferation of
IL-15-stimulated T cells and the secretion of TNF- from
IL-15-stimulated T cell/macrophage cocultures. Rolipram and
8-(4-chlorophenylthio)-cAMP (CPT-cAMP) blocked these increases.
Measurement of protein kinase A (PKA) activity and the use of
inhibitory cAMP analogues (RpCPT-cAMP) confirmed that rolipram worked
by stimulating PKA. These data suggest that PKA-activating agents, such
as rolipram, can block secretion of TNF- from macrophages by
inhibiting T cell activation and expression of surface
molecules.
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