Peer-Reviewed Journal Details
Mandatory Fields
Colleran, A,Ryan, A,O'Gorman, A,Mureau, C,Liptrot, C,Dockery, P,Fearnhead, H,Egan, LJ
2011
July
Journal Of Biological Chemistry
Autophagosomal I kappa B alpha Degradation Plays a Role in the Long Term Control of Tumor Necrosis Factor-alpha-induced Nuclear Factor-kappa B (NF-kappa B) Activity
Published
()
Optional Fields
INFLAMMATORY-BOWEL-DISEASE INTESTINAL PANETH CELLS TRANSCRIPTION FACTOR EPITHELIAL-CELLS FAMILY-MEMBERS CROHN-DISEASE ACTIVATION KINASE INHIBITOR PHOSPHORYLATION
286
22886
22893
Transcription factor NF-kappa B is persistently activated in many chronic inflammatory diseases and cancers. The short term regulation of NF-kappa B is well understood, but little is known about the mechanisms of its long term activation. We studied the effect of a single application of TNF-alpha on NF-kappa B activity for up to 48 h in intestinal epithelial cells. Results show that NF-kappa B remained persistently activated up to 48 h after TNF-alpha and that the long term activation of NF-kappa B was accompanied by a biphasic degradation of I kappa B alpha. The first phase of I kappa B alpha degradation was proteasome-dependent, but the second was not. Further investigation showed that TNF-alpha stimulated formation of autophagosomes in intestinal epithelial cells and that I kappa B alpha co-localized with autophagosomal vesicles. Pharmacological or genetic blockade of autophagosome formation or the inhibition of lysosomal proteases decreased TNF-alpha-induced degradation of I kappa B alpha and lowered NF-kappa B target gene expression. Together, these findings indicate a role of autophagy in the control of long term NF-kappa B activity. Because abnormalities in autophagy have been linked to ineffective innate immunity, we propose that alterations in NF-kappa B may mediate this effect.
DOI 10.1074/jbc.M110.199950
Grant Details
Publication Themes