Opposing effects of proteasomes and lysosomes on LIFR: modulation by TNF.
The blood-brain barrier (BBB), a communicating interface for inflammation, transports cytokines through its endothelial cells. This study shows how tumor necrosis factor alpha (TNF) regulates the expression of the leukemia inhibitor factor receptor (LIFR) gp190 in RBE4 cells. The high expression of LIFR was rapidly downregulated by the proinflammatory agents lipopolysaccharide, TNF, and LIF. Downregulation by TNF affected LIFR endocytosis and lysosomal degradation, preceding decreased LIFR mRNA. Lysosomal inhibitors reversed the rapid disappearance of LIFR, whereas inhibition of the ubiquitin-proteasome pathway did not. Rather, blockade of proteasome activity, as well as inhibition of NFkappaB activation, reduced the basal expression of LIFR. Thus, NFkappaB activity and proteasome degradation of IkappaB stabilized LIFR and prevented its rapid lysosomal degradation. By a non-NFkappaB-mediated mechanism, TNF facilitated LIFR degradation and reduced LIFR activation indicated by pStat3. The novel opposite effects of proteasomes and lysosomes in controlling receptor expression shows the functional implications and interactions of circulating inflammatory cytokines in acutely modulating BBB activity.
Yu
Chuanhui
C
The Blood-Brain Barrier Group, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
Kastin
Abba J
AJ
Tu
Hong
H
Pan
Weihong
W
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology*; D002458:Cell Fractionation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507842:Lifr protein, rat; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex