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This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/R84    most recent 00340.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zhou, M. Articles by Wang, P. PubMed PubMed Citation Articles by Zhou, M. Articles by Wang, P.

INFLAMMATION AND CYTOKINES

Endotoxin downregulates peroxisome proliferator-activated receptor- via the increase in TNF- release

Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center and The Feinstein Institute for Medical Research, Manhasset, New York

Submitted 14 May 2007 ; accepted in final form 1 November 2007

The nuclear receptor peroxisome proliferator-activated receptor- (PPAR-) is anti-inflammatory in a cell-based system and in animal models of endotoxemia. We have shown that PPAR- gene expression is downregulated in macrophages after lipopolysaccharide (LPS) stimulation. However, it remains unknown whether hepatic PPAR- is altered in sepsis and, if so, whether LPS directly downregulates PPAR-. To study this, rats were subjected to sepsis by cecal ligation and puncture (CLP). Hepatic tissues were harvested at 5, 10, and 20 h after CLP. PPAR- gene expression and protein levels were determined by RT-PCR and Western blot analysis, respectively. The results showed that PPAR- gene expression decreased at 10 and 20 h and that its proteins levels were reduced at 20 h after CLP. PPAR- levels were also decreased in animals that were administered LPS. To determine the direct effects of LPS on PPAR- downregulation, LPS binding agent polymyxin B (PMB) was administered intramuscularly after CLP. The administration of PMB significantly reduced plasma levels of endotoxin, but it did not prevent the downregulation of PPAR- expression. We found that circulating levels of TNF- still remained significantly elevated in PMB-treated septic animals. We, therefore, hypothesize that the decrease of PPAR- expression is TNF- dependent. To investigate this, Kupffer cells (KCs) were isolated from normal rats and stimulated with LPS or TNF-. TNF- significantly attenuated PPAR- gene expression in KCs. Although LPS decreased PPAR- in KCs, the downregulatory effect of LPS was blocked by the addition of TNF--neutralizing antibodies. Furthermore, the administration of TNF--neutralizing antibodies to animals before the onset of sepsis prevented the downregulation of PPAR- in sepsis. We, therefore, conclude that LPS downregulates PPAR- expression during sepsis via an increase in TNF- release.

peroxisome proliferator-activated receptor-; liver; Kupffer cells; tumor necrosis factor-; lipopolysaccharide; cecal ligation and puncture