TY - JOUR
T1 - Peroxisome Proliferator Activator Receptor-γ Ligands, 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone, Reduce Systemic Inflammation in Polymicrobial Sepsis by Modulation of Signal Transduction Pathways
AU - Zingarelli, Basilia
AU - Sheehan, Maeve
AU - Hake, Paul W.
AU - O'Connor, Michael
AU - Denenberg, Alvin
AU - Cook, James A.
PY - 2003/12/15
Y1 - 2003/12/15
N2 - Peroxisome proliferator activator receptor-γ (PPARγ) is a nuclear receptor that controls the expression of several genes involved in metabolic homeostasis. We investigated the role of PPARγ during the inflammatory response in sepsis by the use of the PPARγ ligands, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) and ciglitazone. Polymicrobial sepsis was induced by cecal ligation and puncture in rats and was associated with hypotension, multiple organ failure, and 50% mortality. PPARγ expression was markedly reduced in lung and thoracic aorta after sepsis. Immunohistochemistry showed positive staining for nitrotyrosine and poly(ADP-ribose) synthetase in thoracic aortas. Plasma levels of TNF-α, IL-6, and IL-10 were increased. Elevated activity of myeloperoxidase was found in lung, colon, and liver, indicating a massive infiltration of neutrophils. These events were preceded by degradation of inhibitor κBα (IκBα), activation IκB kinase complex, and c-Jun NH2-terminal kinase and, subsequently, activation of NF-κB and AP-1 in the lung. In vivo treatment with ciglitazone or 15d-PGJ2 ameliorated hypotension and survival, blunted cytokine production, and reduced neutrophil infiltration in lung, colon, and liver. These beneficial effects of the PPARγ ligands were associated with the reduction of IκB kinase complex and c-Jun NH2-terminal kinase activation and the reduction of NF-κB and AP-1 DNA binding in the lung. Furthermore, treatment with ciglitazone or 15d-PGJ2 up-regulated the expression of PPARγ in lung and thoracic aorta and abolished nitrotyrosine formation and poly(ADP-ribose) expression in aorta. Our data suggest that PPARγ ligands attenuate the inflammatory response in sepsis through regulation of the NF-κB and AP-1 pathways.
AB - Peroxisome proliferator activator receptor-γ (PPARγ) is a nuclear receptor that controls the expression of several genes involved in metabolic homeostasis. We investigated the role of PPARγ during the inflammatory response in sepsis by the use of the PPARγ ligands, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) and ciglitazone. Polymicrobial sepsis was induced by cecal ligation and puncture in rats and was associated with hypotension, multiple organ failure, and 50% mortality. PPARγ expression was markedly reduced in lung and thoracic aorta after sepsis. Immunohistochemistry showed positive staining for nitrotyrosine and poly(ADP-ribose) synthetase in thoracic aortas. Plasma levels of TNF-α, IL-6, and IL-10 were increased. Elevated activity of myeloperoxidase was found in lung, colon, and liver, indicating a massive infiltration of neutrophils. These events were preceded by degradation of inhibitor κBα (IκBα), activation IκB kinase complex, and c-Jun NH2-terminal kinase and, subsequently, activation of NF-κB and AP-1 in the lung. In vivo treatment with ciglitazone or 15d-PGJ2 ameliorated hypotension and survival, blunted cytokine production, and reduced neutrophil infiltration in lung, colon, and liver. These beneficial effects of the PPARγ ligands were associated with the reduction of IκB kinase complex and c-Jun NH2-terminal kinase activation and the reduction of NF-κB and AP-1 DNA binding in the lung. Furthermore, treatment with ciglitazone or 15d-PGJ2 up-regulated the expression of PPARγ in lung and thoracic aorta and abolished nitrotyrosine formation and poly(ADP-ribose) expression in aorta. Our data suggest that PPARγ ligands attenuate the inflammatory response in sepsis through regulation of the NF-κB and AP-1 pathways.
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U2 - 10.4049/jimmunol.171.12.6827
DO - 10.4049/jimmunol.171.12.6827
M3 - Article
C2 - 14662889
AN - SCOPUS:0346366979
SN - 0022-1767
VL - 171
SP - 6827
EP - 6837
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -