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(Received for publication, November 20, 1995, and in revised form, March 27, 1996)
From the Kennedy Institute of Rheumatology, Sunley Division, 1 Lurgan Ave., Hammersmith, London W6 8LW, United Kingdom and
Interleukin-10 (IL-10) is a powerful suppressor
of the proinflammatory monokine production by
lipopolysaccharide-stimulated monocytes as well as a T- and B-cell
growth cofactor. The signal transduction cascades initiated by IL-10
ligation to its cognate receptor remain to be elucidated. Here, we
demonstrate that in both primary monocytes and the D36 cell line, IL-10
rapidly and transiently stimulated phosphatidylinositol 3-kinase
activity associated with the p85 subunit of the enzyme. IL-10 also
activated p70 S6 kinase in both cell types. The activation of both of
these kinases was sensitive to wortmannin, an inhibitor of
phosphatidylinositol 3-kinase. The activation of p70 S6 kinase was also
inhibited by the immunosuppressive drug rapamycin. Both rapamycin and
wortmannin inhibited the IL-10-induced proliferation of D36 cells but
in contrast had no effect on the antiinflammatory effects of the
cytokine on lipopolysaccharide-stimulated monocytes. Similar results on
D36 proliferation and lipopolysaccharide-stimulated monocyte inhibition
by IL-10 were obtained with another phosphatidylinositol 3-kinase
inhibitor, LY294002. This suggests that the activation of
phosphatidylinositol 3-kinase and p70 S6 kinase is involved in the
proliferative functions of IL-10 and that other as yet uncharacterized
pathways affect the suppressive effects on monocytes, indicating that
multiple and distinct signaling pathways mediate the various
pleiotropic activities of IL-10. Furthermore, these findings suggest
that it may be possible in the future to modulate the antiinflammatory
effects of IL-10 for therapeutic benefit without disrupting other
functions of the cytokine.
Volume 271, Number 27,
Issue of July 5, 1996
pp. 16357-16362
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
Xenova Ltd., 545 Ipswich Road,
Slough, Berkshire SL1 4EQ, United Kingdom
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