NF-kappa B activation in tumor necrosis factor alpha-stimulated neutrophils is mediated by protein kinase Cdelta. Correlation to nuclear Ikappa Balpha.
The transcription factor NF-kappaB is critical for the expression of multiple genes involved in inflammatory responses and apoptosis. However, the signal transduction pathways regulating NF-kappaB activation in human neutrophils in response to stimulation with tumor necrosis factor-alpha (TNFalpha) are undefined. Since recent studies implicated activation of NF-kappaB as well as protein kinase C-delta (PKCdelta) in neutrophil apoptosis, we investigated involvement of PKCdelta in the activation of NF-kappaB in TNFalpha-stimulated neutrophils. Specific inhibition of PKCdelta by rottlerin prevented IkappaBalpha degradation and NF-kappaB activation in TNFalpha-stimulated neutrophils. This regulation of NF-kappaB activation by PKCdelta was specific only for TNFalpha signaling, since lipopolysaccharide- or interleukin-1beta-induced NF-kappaB activation and IkappaBalpha degradation were not inhibited by rottlerin. In addition, we show that in human neutrophils, but not monocytes, IkappaBalpha localizes in significant amounts in the nucleus of unstimulated cells, and the amount of IkappaBalpha in the nucleus, as well as in the cytoplasm, correlates with the NF-kappaB DNA binding. These results suggest that in human neutrophils, the presence of IkappaBalpha in the nucleus may function as a safeguard against initiation of NF-kappaB dependent transcription of pro-inflammatory and anti-apoptotic genes, and represents a distinct and novel mechanism of NF-kappaB regulation.
Vancurova
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I
Division of Neonatal-Perinatal Medicine, Schneider Children's Hospital, Long Island Jewish Medical Center-The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA. vancurov@lij.edu
Miskolci
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Davidson
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D
D000098:Acetophenones / Q000494:pharmacology; D001483:Base Sequence; D001578:Benzopyrans / Q000494:pharmacology; D015342:DNA Probes; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020672:I-kappa B Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051745:Protein Kinase C-delta; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D000098:Acetophenones; D001578:Benzopyrans; D015342:DNA Probes; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007527:Isoenzymes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C085746:rottlerin; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase