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Vol. 296, Issue 1, 181-187, January 2001
"George P. Livanos" Laboratory, Evangelismos Hospital,
Department of Critical Care and Pulmonary Services, University of
Athens, Athens, Greece (A.X., A.P., A.M., M.E., C.R.); and
Laboratory of Biological Chemistry, Medical School, University of
Ioannina, Ioannina, Greece (T.F.)
Flavonoids are naturally occurring polyphenolic compounds with a wide
distribution throughout the plant kingdom. In the present study, we
compared the ability of several flavonoids to modulate the production
of proinflammatory molecules from lipopolysaccharide (LPS)-stimulated
macrophages and investigated their mechanism(s) of action. Pretreatment
of RAW 264.7 with luteolin, luteolin-7-glucoside, quercetin, and the
isoflavonoid genistein inhibited both the LPS-stimulated TNF-
and
interleukin-6 release, whereas eriodictyol and hesperetin only
inhibited TNF- release. From the compounds tested luteolin and
quercetin were the most potent in inhibiting cytokine production with
an IC50 of less than 1 and 5 µM for TNF- release,
respectively. To determine the mechanisms by which flavonoids inhibit
LPS signaling, we used luteolin and determined its ability to interfere
with total protein tyrosine phosphorylation as well as Akt
phosphorylation and nuclear factor-
B activation. Pretreatment of the
cells with luteolin attenuated LPS-induced tyrosine phosphorylation of
many discrete proteins. Moreover, luteolin inhibited LPS-induced
phosphorylation of Akt. Treatment of macrophages with LPS resulted in
increased IB- phosphorylation and reduced the levels of
IB-. Pretreatment of cells with luteolin abolished the effects of
LPS on IB-. To determine the functional relevance of the
phosphorylation events observed with IB-, macrophages were
transfected either with a control vector or a vector coding for the
luciferase reporter gene under the control of B
cis-acting elements. Incubation of transfected RAW 264.7 cells with LPS increased luciferase activity in a luteolin-sensitive
manner. We conclude that luteolin inhibits protein tyrosine
phosphorylation, nuclear factor-B-mediated gene expression and
proinflammatory cytokine production in murine macrophages.
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