PPARgamma inhibits NF-kappaB-dependent transcriptional activation in skeletal muscle.
Skeletal muscle pathology associated with a chronic inflammatory disease state (e.g., skeletal muscle atrophy and insulin resistance) is a potential consequence of chronic activation of NF-kappaB. It has been demonstrated that peroxisome proliferator-activated receptors (PPARs) can exert anti-inflammatory effects by interfering with transcriptional regulation of inflammatory responses. The goal of the present study, therefore, was to evaluate whether PPAR activation affects cytokine-induced NF-kappaB activity in skeletal muscle. Using C(2)C(12) myotubes as an in vitro model of myofibers, we demonstrate that PPAR, and specifically PPARgamma, activation potently inhibits inflammatory mediator-induced NF-kappaB transcriptional activity in a time- and dose-dependent manner. Furthermore, PPARgamma activation by rosiglitazone strongly suppresses cytokine-induced transcript levels of the NF-kappaB-dependent genes intracellular adhesion molecule 1 (ICAM-1) and CXCL1 (KC), the murine homolog of IL-8, in myotubes. To verify whether muscular NF-kappaB activity in human subjects is suppressed by PPARgamma activation, we examined the effect of 8 wk of rosiglitazone treatment on muscular gene expression of ICAM-1 and IL-8 in type 2 diabetes mellitus patients. In these subjects, we observed a trend toward decreased basal expression of ICAM-1 mRNA levels. Subsequent analyses in cultured myotubes revealed that the anti-inflammatory effect of PPARgamma activation is not due to decreased RelA translocation to the nucleus or reduced RelA DNA binding. These findings demonstrate that muscle-specific inhibition of NF-kappaB activation may be an interesting therapeutic avenue for treatment of several inflammation-associated skeletal muscle abnormalities.
Remels
A H V
AH
Department of Respiratory Medicine, Maastricht University, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. a.remels@pul.unimaas.nl
Langen
R C J
RC
Gosker
H R
HR
Russell
A P
AP
Spaapen
F
F
Voncken
J W
JW
Schrauwen
P
P
Schols
A M W J
AM
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
D016207:Cytokines; C425931:GW 501516; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D016328:NF-kappa B; D047495:PPAR gamma; D011743:Pyrimidines; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C006253:pirinixic acid