Dipyrithione inhibits lipopolysaccharide-induced iNOS and COX-2 up-regulation in macrophages and protects against endotoxic shock in mice.
Dipyrithione (PTS2) possesses anti-bacterial and anti-fungal activity. In the present study, we found that PTS2 dose-dependently inhibited the LPS-induced up-regulation of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein level in RAW264.7 cells. RT-PCR experiments showed that PTS2 suppressed LPS-induced iNOS but not COX-2 expression at the mRNA level. As expected, PTS2 prevented NO secretion in RAW264.7 cells. Furthermore, PTS2 administration significantly decreased LPS-induced mortality in mice. Mechanistically, PTS2 decreased expression and phosphorylation of STAT1, but did not interfere with the MAPK and NF-kappaB pathways. In conclusion, PTS2 protects mice against endotoxic shock and inhibits LPS-induced production of pro-inflammatory mediators, suggesting that PTS2 could play an anti-inflammatory role in response to LPS.
Liu
Ziwen
Z
Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210097, PR China.
Fan
Yumei
Y
Wang
Yu
Y
Han
Cui
C
Pan
Yu
Y
Huang
Huang
H
Ye
Ying
Y
Luo
Lan
L
Yin
Zhimin
Z
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012772:Shock, Septic / Q000517:prevention & control*; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011725:Pyridines; D050794:STAT1 Transcription Factor; D009569:Nitric Oxide; C032196:dipyrithione; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D020929:Mitogen-Activated Protein Kinase Kinases