Peroxisome proliferator activated receptor gamma is not necessary for the development of LPS-induced tolerance in macrophages.
Peroxisome proliferator activated receptor-gamma (PPARgamma) has been reported to exert anti-inflammatory properties in endotoxic shock and sepsis. One phenomenon that alters the inflammatory response to endotoxin [lipopolysaccharide (LPS)] is endotoxin tolerance, which is caused by previous exposure to endotoxin. Here, we investigate whether changes in endogenous PPARgamma function regulate this phenomenon using three different models of LPS-induced tolerance in macrophages. In a first in vitro model, previous LPS exposure of murine J774.2 macrophages suppressed tumour necrosis factor-alpha (TNF-alpha) release in response to subsequent LPS challenge. Treatment of J774.2 cells with the PPARgamma inhibitor GW9662 did not alter tolerance induction because these cells were still hyporesponsive to the secondary LPS challenge. In a second ex vivo model, primary rat peritoneal macrophages from LPS-primed rats exhibited suppression of thromboxane B2 and TNF-alpha production, while maintaining nitrite production in response to in vitro LPS challenge. Pretreatment of rats with the PPARgamma inhibitor GW9662 in vivo failed to alter the tolerant phenotype of these primary macrophages. In a third ex vivo model, primary peritoneal macrophages with conditional deletion of PPARgamma were harvested from LPS-primed Cre-lox mice (Cre+/+ PPARgamma-/-) and exhibited significant suppression of TNF-alpha production in response to in vitro LPS challenge. Furthermore, both LPS-primed PPARgamma-deficient Cre+/+ PPARgamma-/- mice and wild-type Cre-/- PPARgamma+/+ mice exhibited reduced plasma TNF-alpha levels in response to a high dose of LPS in vivo. These data demonstrate that PPARgamma does not play a role in the LPS-induced tolerant phenotype in macrophages.
Zingarelli
Basilia
B
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. basilia.zingarelli@cchmc.org
Fan
Hongkuan
H
Ashton
Sarah
S
Piraino
Giovanna
G
Mangeshkar
Prajakta
P
Cook
James A
JA
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000276:immunology*; D051381:Rats; D020318:Rats, Long-Evans; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D008070:Lipopolysaccharides; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha