Suppression of NF-kappaB activation and cytokine production by N-acetylcysteine in pancreatic acinar cells.
Reactive oxygen species (ROS), generated by infiltrating neutrophils, are considered as an important regulator in the pathogenesis and development of pancreatitis. A hallmark of the inflammatory response is the induction of cytokine gene expression, which may be regulated by oxidant-sensitive transcription factor, nuclear factor-kappaB (NF-kappaB). Present study aims to investigate whether neutrophils primed by 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA) affect the productions of H(2)O(2) and lipid peroxide (LPO), NF-kappaB activation and cytokine production in pancreatic acinar cells, and whether these alterations were inhibited by N-acetylcysteine (NAC) and superoxide dismutase (SOD). Neutrophils generated ROS by stimulation with PMA, which was inhibited by NAC and SOD. In acinar cells, PMA-primed neutrophils increased the productions of H(2)O(2), LPO, and cytokines both time and dose dependently. PMA-primed neutrophils resulted in the activation of two species of NF-kappaB dimers (a p50/p65 heterodimer and a p50 homodimer) in acinar cells. Both NAC and SOD inhibited neutrophil-induced, oxidant-mediated alterations in acinar cells. In conclusion, ROS, generated by neutrophils, activates NF-kappaB, resulting in upregulation of inflammatory cytokines in acinar cells. Antioxidants such as NAC might be useful antiinflammatory agents by inhibiting oxidant-mediated activation of NF-kappaB and decreasing cytokine production.
Kim
H
H
Department of Pharmacology and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea.
Seo
J Y
JY
Roh
K H
KH
Lim
J W
JW
Kim
K H
KH
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D000975:Antioxidants; D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D013755:Tetradecanoylphorbol Acetate; D000111:Acetylcysteine