Dipyrithione inhibits lipopolysaccharide-induced iNOS and COX-2 up-regulation in macrophages and protects against endotoxic shock in mice

Abstract 

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-κB 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.

Abbreviations: PTS2, dipyrithione, LPS, lipopolysaccharide, iNOS, inducible nitric oxide synthase, NO, nitric oxide, COX-2, cyclooxygenase-2, STAT1, signal transducers and activators of transcription 1, MAPKs, mitogen-activated protein kinases, NF-κB, nuclear factor κB, ERK, extracellular signal-regulated kinase, JNK, c-Jun N-terminal kinase

Keywords: Dipyrithione, Lipopolysaccharide, iNOS, COX-2, STAT1, Endotoxic shock