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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 208-216
Mechanism of Interleukin-10 Inhibition of T-Helper Cell
Activation by Superantigen at the Level of the Cell Cycle
George Q. Perrin,
Howard M. Johnson, and
Prem S. Subramaniam
From the Department of Microbiology and Cell Science, University of
Florida, Gainesville, FL.
We have analyzed the effects of interleukin-10 (IL-10) on the entry
of quiescent CD4+ T cells into the cell cycle upon
stimulation with the superantigen staphylococcal enterotoxin B (SEB).
IL-10 arrested cells at G0/G1. IL-10 treatment
prevented the downregulation of p27Kip1, an inhibitory
protein that controls progression out of the G0 phase of
the cell cycle. IL-10 also prevented the upregulation of the
G1 cyclins D2 and D3, proteins necessary for entry and progression through the G1 phase of the cell cycle.
Associated with the inhibition of the cell cycle, IL-10 suppressed SEB
induction of interleukin-2 (IL-2). Addition of exogenous IL-2 to
IL-10-treated cells significantly reversed the antiproliferative
effects of IL-10. Moreover, IL-10 effects on the early G1
proteins p27Kip1 and cyclin D2 were similarly reversed by
exogenous IL-2. Although this reversal by IL-2 was pronounced, it was
not complete, suggesting that IL-10 may have some effects not directly
related to the suppression of IL-2 production. Cell separation
experiments suggest that IL-10 can effect purified CD4+ T
cells directly, providing functional evidence for the presence of IL-10
receptors on CD4+ T cells. IL-10 also inhibited
expression of IL-2 transcriptional regulators c-fos and c-jun, which
also inhibit other cell functions. Our studies show that the mechanism
of IL-10 regulation of quiescent CD4+ T-cell activation
is mainly by blocking induction of IL-2 that is critical to
downregulation of p27Kip1 and upregulation of D cyclins in
T-cell activation and entry into the cell cycle.
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