The PPARdelta agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibition.
BACKGROUND
Interleukin-6 and downstream liver effectors acute phase reactants are implicated in the systemic inflammatory reaction. Peroxisome proliferator-activated receptor delta (PPARdelta), which binds to and is activated by a variety of fatty acids, was recently shown to have anti-inflammatory actions.


METHODS
We examined the ability of the synthetic PPARdelta 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 alpha1-antichymotrypsin in HepG2 cells. The compound also suppressed interleukin-6-induced mRNA expression of alpha2-acid glycoprotein, beta-fibrinogen and alpha2-macroglobulin in and the secretion of C-reactive protein by rat primary hepatocytes. Depletion of the PPARdelta receptor, but not of PPARalpha or gamma, attenuated the suppressive effect of GW501516 on interleukin-6-induced alpha1-antichymotrypsin mRNA expression, indicating that PPARdelta specifically mediated this effect. Since interleukin-6 stimulates the transcriptional activity of the alpha1-antichymotrypsin promoter by activating the signal transducer and activator of transcription (STAT) 3, we examined functional interaction of this transcription factor and PPARdelta on this promoter. Overexpression of PPARdelta enhanced the suppressive effect of GW501516 on STAT3-activated transcriptional activity of the alpha1-antichymotrypsin promoter, while GW501516 suppressed interleukin-6-induced binding of this transcription factor to this promoter.


CONCLUSIONS
These findings indicate that agonist-activated PPARdelta interferes with interleukin-6-induced acute phase reaction in the liver by inhibiting the transcriptional activity of STAT3. PPARdelta agonists might be useful for the suppression of systemic inflammatory reactions in which IL-6 plays a central role.
Kino
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National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1109, USA.
Rice
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Chrousos
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D000209:Acute-Phase Proteins / Q000378:metabolism; D000210:Acute-Phase Reaction / Q000209:etiology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology*; D000093242:Interleukin-6 Inhibitors
D000209:Acute-Phase Proteins; D047494:PPAR delta; D050796:STAT3 Transcription Factor; D013844:Thiazoles; D000093242:Interleukin-6 Inhibitors; C425931:GW 501516