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.