Butyrate suppression of colonocyte NF-kappa B activation and cellular proteasome activity.
Butyrate is derived from the microbial metabolism of dietary fiber in the colon where it plays an important role in linking colonocyte turnover and differentiation to luminal content. In addition, butyrate appears to have both anti-inflammatory and cancer chemopreventive activities. Using confocal microscopy and cell fractionation studies, butyrate pretreatment of a human colon cell line (HT-29 cells) inhibited the tumor necrosis factor-alpha (TNF-alpha)-induced nuclear translocation of the proinflammatory transcription factor NF-kappaB. Butyrate inhibited NF-kappaB DNA binding within 30 min of TNF-alpha stimulation, consistent with an inhibition of nuclear translocation. IkappaB.NF-kappaB complexes extracted from butyrate-treated cells were relatively resistant to in vitro dissociation by deoxycholate, suggesting a change in cellular IkappaB composition. Butyrate treatment increased p100 expression, an IkappaB that was not degraded upon TNF-alpha treatment. Butyrate also reduced the extent of TNF-alpha-induced IkappaB-alpha degradation and enhanced the presence of ubiquitin-conjugated IkappaB-alpha. The suppression of IkappaB-alpha degradation corresponded with a reduction in cellular proteasome activity as determined by in vitro proteasome assays and the increased presence of ubiquitin-conjugated proteins. The butyrate suppression of IkappaB-alpha degradation and proteasome activity may derive from its ability to inhibit histone deacetylases since the specific deacetylase inhibitor trichostatin A had similar effects. These results suggest a potential mechanism for the anti-inflammatory activity of butyrate and demonstrate the interplay between short chain fatty acids and cellular proteasome activity.
Yin
L
L
Department of Molecular and Cellular Biology, University of Connecticut, Storrs, Connecticut 06269, USA.
Laevsky
G
G
Giardina
C
C
D021581:Active Transport, Cell Nucleus; D002087:Butyrates / Q000494:pharmacology*; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003106:Colon / Q000166:cytology* / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003840:Deoxycholic Acid / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020672:I-kappa B Proteins; D015151:Immunoblotting; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009097:Multienzyme Complexes / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002087:Butyrates; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D006877:Hydroxamic Acids; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D003840:Deoxycholic Acid; D000072000:NF-KappaB Inhibitor alpha; C012589:trichostatin A; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases