Modulation of peripheral inflammation in sensory ganglia by nuclear factor (kappa)B decoy oligodeoxynucleotide: involvement of SRC kinase pathway.
Nuclear factor kappa B (NF(kappa)B) transcription factor plays a key role in the expression of many genes involved in the inflammatory process. We used the Freund's Complete Adjuvant (FCA)-induced model of peripheral inflammation to investigate the anti-inflammatory effects of double stranded oligodeoxynucleotides (ODN) with consensus NF(kappa)B sequence as transcription factor decoys to inhibit NF(kappa)kappaB activation in the dorsal root ganglia (DRG). Local administration of the wild-type-, but not mutant-ODN decoy, dose-dependently inhibited edema formation and paw withdrawal latency as a measure of hyperalgesic response induced by FCA in rat paw. Biochemical assays performed in ipsilateral L4/L5 dorsal root ganglia obtained following FCA/wild-type ODN treatment showed: (1) an inhibition of the activity of c-Src kinase, a member of the non-receptor tyrosine kinase super family, (2) a decreased level of p65 NF(kappa)B subunit, and (3) an inhibition of cyclooxygenase-2 (COX-2) protein expression, a major pro-inflammatory enzyme transcriptionally controlled by NF(kappa)B. The present results indicate that the wild-type ODN decoy may act as a competitor for NF(kappa)B binding to its cognate recognition sequence as well as a modulator of c-Src activity in the DRG. The NF(kappa)B/c-Src interaction may represent a novel pathway for further exploring the molecular mechanism of inflammatory pain.
Igwe
Orisa J
OJ
M3-104, Division of Pharmacology, 2411 Holmes Street, UMKC School of Pharmacy and Medicine, University of Missouri-Kansas City, Kansas City, MO 64108-2792, USA. igweo@umkc.edu
D000818:Animals; D005620:Freund's Adjuvant; D005727:Ganglia, Spinal / Q000503:physiopathology*; D020868:Gene Silencing; D006930:Hyperalgesia / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D008297:Male; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014162:Transfection / Q000379:methods; D019061:src-Family Kinases / Q000378:metabolism*
D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D005620:Freund's Adjuvant; D019061:src-Family Kinases