Tempol reduces the activation of nuclear factor-kappaB in acute inflammation.
Recent studies have demonstrated that Tempol, a membrane-permeable radical scavenger, exerts protective effects in various models of inflammation and shock. Since nuclear factor-kappaB (NF-kappaB) is a transcription factor, which plays a pivotal role in the induction of genes involved in physiological processes as well as in the response to inflammation, we have investigated the effect of Tempol on NF-kappaB activation in a model of acute inflammation in mice. Injection of carrageenan into the pleural cavity of mice induced an acute inflammatory response characterized by fluid accumulation in the pleural cavity, which contained a large number of neutrophils, as well as an increased production of tumor necrosis factor-alpha, (TNF-alpha) and interleukin-1alpha (IL-1alpha). Tempol (100mg/kg i.p 30min prior to carrageenan administration) significantly attenuated the degree of pleuritis caused by carageeenan (all parameters measured). Administration of carageeenan into the chest cavity (pleuritis) was associated with the activation of NF-kappaB in the lung. In particular, the appearance of IkappaB-alpha in homogenates of lung tissue was investigated by immunoblot analysis at 4h after carrageenan administration. IkappaB-alpha levels were substantially reduced in the lung tissue from carrageenan-treated mice in comparison with sham-treated mice. Furthermore, to detect any effects of Tempol on NF-kappaB/DNA binding, lung extracts were analyzed by EMSA. The DNA binding activity significantly increased in extracts obtained from lungs of vehicle-treated mice at 4h after carrageenan administration. Treatment of mice with Tempol caused a significant inhibition of carrageenan-induced IkappaB-alpha degradation and NF-kappaB/DNA binding activity. These data confirm that Tempol exerts potent anti-inflammatory properties and clearly demonstrates for the first time that Tempol reduces the activation of NF-kappaB in vivo.
Cuzzocrea
Salvatore
S
Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy. salvator@unime.it
Pisano
Barbara
B
Dugo
Laura
L
Ianaro
Angela
A
Patel
Nimesh S A
NS
Caputi
Achille P
AP
Thiemermann
Christoph
C
D000208:Acute Disease; D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D051550:I-kappa B Kinase; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013113:Spin Labels; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
D003497:Cyclic N-Oxides; D007375:Interleukin-1; D016328:NF-kappa B; D013113:Spin Labels; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; C001803:tempol