NCX 4040, a nitric oxide-donating aspirin derivative, inhibits Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages.
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.
Department of Biological Science, College of Medical and Life Sciences, Silla University, Busan, Korea.
Eun-Young
EY
Choi
Department of Biological Science, College of Medical and Life Sciences, Silla University, Busan, Korea.
So-Hui
SH
Choe
Department of Biological Science, College of Medical and Life Sciences, Silla University, Busan, Korea.
Jin-Yi
JY
Hyeon
Department of Oral Pathology, School of Dentistry, Pusan National University, Yangsan, Gyeongsangnam-do, Korea; Institute of Translational Dental Sciences, Pusan National University, Yangsan, Gyeongsangnam-do, Korea.
Hae Ryoun
HR
Park
Department of Periodontology, School of Dentistry, Pusan National University, Yangsan, Gyeongsangnam-do, Korea; Dental Research Institute, Pusan National University Dental Hospital, Yangsan, Gyeongsangnam-do, Korea.
Jeom-Il
JI
Choi
Department of Biological Science, College of Medical and Life Sciences, Silla University, Busan, Korea.
In Soon
IS
Choi
Department of Periodontology, School of Dentistry, Pusan National University, Yangsan, Gyeongsangnam-do, Korea; Dental Research Institute, Pusan National University Dental Hospital, Yangsan, Gyeongsangnam-do, Korea; Institute of Translational Dental Sciences, Pusan National University, Yangsan, Gyeongsangnam-do, Korea. Electronic address: sungjokim@pusan.ac.kr.
Sung-Jo
SJ
Kim
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D009574:Nitro Compounds / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D018713:Prevotella intermedia / Q000737:chemistry*; D000067996:RAW 264.7 Cells; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C498045:NCX 4040; D016328:NF-kappa B; D009574:Nitro Compounds; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D009569:Nitric Oxide; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001241:Aspirin
HO-1; Lipopolysaccharide; NCX 4040; NF-κB; Proinflammatory mediators; SOCS1; STAT