NF-kappa B activation in tumor necrosis factor alpha-stimulated neutrophils is mediated by protein kinase C delta - Correlation to nuclear I kappa B alpha

The transcription factor NF-kappaB is critical for the expression of multip le genes involved in inflammatory responses and apoptosis. However, the sig nal transduction pathways regulating NF-kappaB activation in human neutroph ils in response to stimulation with tumor necrosis factor-alpha (TNF alpha) are undefined. Since recent studies implicated activation of NP-kappaB as well as protein kinase C-delta (PKC delta) in neutrophil apoptosis, we inve stigated involvement of PKC delta in the activation of NF-kappaB in TNF alp ha -stimulated neutrophils. Specific inhibition of PKC delta by rottlerin p revented I kappaB alpha degradation and NF-kappaB activation in TNF alpha - stimulated neutrophils. This regulation of NF-kappaB activation by PKC delt a was specific only for TNF alpha signaling, since lipopolysaccharide- or i nterleukin-1 beta -induced NF-kappaB activation and I kappaB alpha degradat ion were not inhibited by rottlerin. In addition, we show that in human neu trophils, but not monocytes, I kappaB alpha localizes in significant amount s in the nucleus of unstimulated cells, and the amount of I kappaB alpha in the nucleus, as well as in the cytoplasm, correlates with the NF-kappaB DN A binding. These results suggest that in human neutrophils, the presence of I kappaB alpha in the nucleus may function as a safeguard against initiati on of NF-kappaB dependent transcription of pro-inflammatory and anti-apopto tic genes, and represents a distinct and novel mechanism of NF-kappaB regul ation.