NCX 4040, a nitric oxide-donating aspirin derivative, inhibits Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages.

Abstract

In this study, the effects and underlying mechanisms of NCX 4040, a nitric oxide (NO)-donating aspirin derivative, on the production of proinflammatory mediators were examined using murine macrophages exposed to lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen implicated in the etiology of periodontal disease. NCX 4040 significantly reduced P. intermedia LPS-induced production of inducible NO synthase (iNOS)-derived NO, IL-1β and IL-6 as well as their mRNA expression in RAW264.7 cells. Notably, NCX 4040 was much more effective than the parental compound aspirin in reducing LPS-induced production of inflammatory mediators. NCX 4040 induced the expression of heme oxygenase-1 (HO-1) in cells treated with P. intermedia LPS, and the suppressive effect of NCX 4040 on LPS-induced NO production was significantly reversed by SnPP, a competitive HO-1 inhibitor. NCX 4040 did not influence LPS-induced phosphorylation of JNK and p38. IκB-α degradation as well as nuclear translocation and DNA-binding activities of NF-κB p65 and p50 subunits induced by P. intermedia LPS were significantly reduced by NCX 4040. Besides, LPS-induced phosphorylation of STAT1 and STAT3 was significantly down-regulated by NCX 4040. Further, NCX 4040 elevated the SOCS1 mRNA in cells stimulated with LPS. This study indicates that NCX 4040 inhibits P. intermedia LPS-induced production of NO, IL-1β and IL-6 in murine macrophages through anti-inflammatory HO-1 induction and suppression of NF-κB, STAT1 and STAT3 activation, which is associated with the activation of SOCS1 signaling. NCX 4040 could potentially be a promising tool in the treatment of periodontal disease, although further studies are required to verify this.

• Authors: Eun-Young Choi, So-Hui Choe, Jin-Yi Hyeon, Hae Ryoun Park, Jeom-Il Choi, In Soon Choi, Sung-Jo Kim
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 768 Pg. 87-95 (Dec 05 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 26511379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Inflammation Mediators
• Lipopolysaccharides
• Membrane Proteins
• NCX 4040
• NF-kappa B
• Nitro Compounds
• STAT1 Transcription Factor
• STAT3 Transcription Factor
• Nitric Oxide
• Heme Oxygenase-1
• Hmox1 protein, mouse
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Aspirin

Topics

• Animals
• Aspirin (analogs & derivatives, metabolism, pharmacology)
• Enzyme Induction (drug effects)
• Heme Oxygenase-1 (biosynthesis)
• Inflammation Mediators (metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, metabolism)
• Membrane Proteins (biosynthesis)
• Mice
• NF-kappa B (metabolism)
• Nitric Oxide (biosynthesis)
• Nitro Compounds (metabolism, pharmacology)
• Phosphorylation (drug effects)
• Prevotella intermedia (chemistry)
• RAW 264.7 Cells
• STAT1 Transcription Factor (metabolism)
• STAT3 Transcription Factor (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)