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Granulocyte colony-stimulating factor downregulates allogeneic immune
responses by posttranscriptional inhibition of tumor necrosis factor- alpha
production
A Kitabayashi, M Hirokawa, Y Hatano, M Lee, J Kuroki, H Niitsu and AB Miura
Department of Internal Medicine, Akita University School of Medicine,
Japan.
We report downregulatory effects of granulocyte colony-stimulating factor
(G-CSF) on allogeneic immune responses in vitro. G-CSF did not affect the
proliferative response of peripheral blood mononuclear cells (PBMC) against
allogeneic Daudi cells but did inhibit tumor necrosis factor (TNF)-alpha
secretion. In contrast with G-CSF, granulocyte- macrophage (GM)-CSF and
interleukin (IL)-3 enhanced alloactivation- induced TNF-alpha production.
G-CSF-mediated suppression of TNF-alpha production was not affected by
fixation of stimulators. G-CSF did not inhibit TNF-alpha mRNA expression or
accelerate mRNA degradation, whereas pentoxifylline inhibited the
expression of TNF-alpha mRNA. These results indicate that G-CSF acts
directly on responder cells and modulates TNF-alpha production at
posttranscriptional levels. Suppression of TNF-alpha secretion was
accompanied by an increase of intracellular cyclic adenosine monophosphate
(cAMP) concentration in alloactivated PBMC. The cell-permeable cAMP
analogue, dibutyryl cAMP, suppressed TNF-alpha secretion without affecting
TNF-alpha mRNA expression. G-CSF showed an inhibitory effect on the
development of cytotoxic effector cells against allogeneic Daudi cells.
Anti-TNF-alpha monoclonal antibody (MoAb) also inhibited the induction of
cytolytic activity, and the inhibitory effects of G-CSF and anti-TNF-alpha
MoAb on killer activity generation were overcome by adding exogenous TNF-
alpha. Hence, impaired generation of cytolytic effector cells by G-CSF is
believed to be the result of reduced TNF-alpha production. Collectively,
the results described above suggest that G-CSF downregulates allogeneic
immune responses by posttranscriptionally inhibiting TNF-alpha production.
Volume 86,
Issue 6,
pp. 2220-2227,
09/15/1995
Copyright © 1995 by The American Society of Hematology

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