Peroxisome proliferator activated receptor γ is not necessary for the development of LPS-induced tolerance in macrophages

Peroxisome proliferator activated receptor-γ (PPARγ) 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 PPARγ 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-α (TNF-α) release in response to subsequent LPS challenge. Treatment of J774.2 cells with the PPARγ 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-α production, while maintaining nitrite production in response to in vitro LPS challenge. Pretreatment of rats with the PPARγ 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 PPARγ were harvested from LPS-primed Cre-lox mice (Cre+/+ PPARγ−/−) and exhibited significant suppression of TNF-α production in response to in vitro LPS challenge. Furthermore, both LPS-primed PPARγ-deficient Cre+/+ PPARγ−/− mice and wild-type Cre−/− PPARγ+/+ mice exhibited reduced plasma TNF-α levels in response to a high dose of LPS in vivo. These data demonstrate that PPARγ does not play a role in the LPS-induced tolerant phenotype in macrophages