TY - JOUR
TI - The PPAR delta agonist GW501516 suppresses interleukin-6-mediated
hepatocyte acute phase reaction via STAT3 inhibition
AU - Kino, T.
AU - Rice, K. C.
AU - Chrousos, G. P.
JO - European Journal of Clinical Investigation
PY - 2007
VL - 37
TODO - 5
SP - 425-433
PB - Blackwell Publishing Inc.
SN - 0014-2972, 1365-2362
TODO - 10.1111/j.1365-2362.2007.01796.x
TODO - alpha 1-antichymotrypsin; inflammation; interleukin-6; peroxisome
proliferator-activated receptor delta (PPAR delta); signal transducer
and activator of transcription 3 (STAT3)
TODO - Background Interleukin-6 and downstream liver effectors acute phase
reactants are implicated in the systemic inflammatory reaction.
Peroxisome proliferator-activated receptor delta (PPAR delta), which
binds to and is activated by a variety of fatty acids, was recently
shown to have anti-inflammatory actions.
Materials and methods We examined the ability of the synthetic PPAR
delta agonist GW501516 to suppress interleukin-6-induced expression of
acute phase proteins in human hepatoma HepG2 cells and rat primary
hepatocytes.
Results GW501516 dose-dependently suppressed interleukin-6-induced mRNA
expression of the acute phase protein alpha 1-antichymotrypsin in HepG2
cells. The compound also suppressed interleukin-6-induced mRNA
expression of alpha 2-acid glycoprotein, beta-fibrinogen and alpha
2-macroglobulin in and the secretion of C-reactive protein by rat
primary hepatocytes. Depletion of the PPAR delta receptor, but not of
PPAR alpha or gamma, attenuated the suppressive effect of GW501516 on
interleukin-6-induced alpha 1-antichymotrypsin mRNA expression,
indicating that PPAR delta specifically mediated this effect. Since
interleukin-6 stimulates the transcriptional activity of the alpha
1-antichymotrypsin promoter by activating the signal transducer and
activator of transcription (STAT) 3, we examined functional interaction
of this transcription factor and PPAR delta on this promoter.
Overexpression of PPAR delta enhanced the suppressive effect of GW501516
on STAT3-activated transcriptional activity of the alpha
1-antichymotrypsin promoter, while GW501516 suppressed
interleukin-6-induced binding of this transcription factor to this
promoter.
Conclusions These findings indicate that agonist-activated PPAR delta
interferes with interleukin-6-induced acute phase reaction in the liver
by inhibiting the transcriptional activity of STAT3. PPAR delta agonists
might be useful for the suppression of systemic inflammatory reactions
in which IL-6 plays a central role.
ER -