Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha activator fenofibrate.
The peroxisome proliferator-activated receptor alpha (PPARalpha), which is highly expressed in liver, plays key roles in lipid metabolism and inflammation. Interleukin-6 (IL-6) is the principal inducer of acute phase response (APR) gene expression. In the present study, we demonstrate that chronic treatment with the PPARalpha agonist fenofibrate fully prevents the IL-6-induced APR gene expression in wild-type but not in PPARalpha-deficient mice. PPARalpha prevents the IL-6-induced expression of the positive APR genes fibrinogen-alpha, -beta, -gamma, haptoglobulin, and serum amyloid A and the IL-6-induced suppression of the negative APR gene, major urinary protein. Furthermore, the effect of PPARalpha on the APR gene expression does not simply consist in a delayed systemic response to IL-6 but occurs directly at the transcriptional level. This global suppression of acute phase gene transcription may be explained by two PPARalpha-dependent in vivo effects: 1) PPARalpha activation results in the down-regulation of the IL-6 receptor components gp80 and gp130 in the liver, thereby reducing the phosphorylation and activation of the downstream transcription factors STAT3 and c-Jun that transduce the IL-6 signal; and 2) PPARalpha reduces the basal expression of the transcription factors CCAAT enhancer-binding protein-alpha, -beta, -delta, which are responsible for immediate and maintained transcription of APR genes. A similar global effect of fenofibrate on acute phase protein expression is observed in hyperlipidemic patients chronically treated with fenofibrate, which displayed decreased plasma concentrations of the positive APR proteins fibrinogen, C-reactive protein, serum amyloid A, plasminogen, and alpha2-macroglobulin and increased plasma concentrations of the negative APR albumin, underlining the clinical significance of our findings.
Gervois
Philippe
P
Gaubius Laboratory, TNO-Prevention and Health, Zernikedreef 9, P. O. Box 2215, 2301 CE Leiden, The Netherlands. pgervois@pharma.univ-lille2.fr
Kleemann
Robert
R
Pilon
Antoine
A
Percevault
Frédéric
F
Koenig
Wolfgang
W
Staels
Bart
B
Kooistra
Teake
T
D000210:Acute-Phase Reaction / Q000235:genetics; D000818:Animals; D001053:Apolipoproteins / Q000037:antagonists & inhibitors; D015536:Down-Regulation / Q000187:drug effects; D011345:Fenofibrate / Q000008:administration & dosage*; D005340:Fibrinogen / Q000037:antagonists & inhibitors; D006242:Haptoglobins / Q000037:antagonists & inhibitors; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000172:deficiency / Q000235:genetics*; D000685:Serum Amyloid A Protein / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000819:agonists / Q000172:deficiency / Q000235:genetics*
D001053:Apolipoproteins; D006242:Haptoglobins; D000960:Hypolipidemic Agents; D015850:Interleukin-6; D018160:Receptors, Cytoplasmic and Nuclear; D000685:Serum Amyloid A Protein; D014157:Transcription Factors; D005340:Fibrinogen; D011345:Fenofibrate