The luminal short-chain fatty acid butyrate modulates NF-kappaB activity in a human colonic epithelial cell line.
OBJECTIVE
The transcription factor nuclear factor-kappaB (NF-kappaB) plays a central role in regulating immune and inflammatory responses. Because butyrate deficiency has been associated with inflammatory bowel disease, we examined the effect of butyrate on NF-kappaB activity in the human HT-29 colonic cell line.


METHODS
The influence of butyrate (4 mmol/L) on NF-kappaB activity was determined using the gel mobility shift assay. The effect of butyrate on the expression of NF-kappaB subunits and inhibitory proteins was determined by immunoblotting. NF-kappaB-regulated gene expression was assayed by primer extension of intercellular adhesion molecule 1 and Mn superoxide dismutase messenger RNA, and by analysis of a transfected luciferase reporter.


RESULTS
Exposure of HT-29 cells to butyrate eliminated their constitutive NF-kappaB, p50 dimer activity. This inhibition corresponded with a reduction in p50 nuclear localization, without a reduction in expression. Butyrate also selectively modulated activation of NF-kappaB, suppressing its activation by tumor necrosis factor alpha and phorbol ester more than 10-fold, without affecting the activity induced by interleukin (IL)-1beta. Butyrate did, however, enhance formation of the stronger p65-p50 transcriptional activator in IL-1beta-stimulated cells. The changes in NF-kappaB activation did not correlate with changes in IkappaBalpha levels. Gene expression reflected DNA binding. The influence of butyrate on NF-kappaB may result in part from its ability to inhibit deacetylases because the specific deacetylase inhibitor trichostatin A has a similar effect.


CONCLUSIONS
These findings suggest that the influences of butyrate on colonic inflammatory responses may result in part from its influence on NF-kappaB activation. This activity of butyrate apparently involves its ability to inhibit deacetylases.
Inan
M S
MS
Department of Molecular Biology, University of Connecticut, Storrs, Connecticut, USA.
Rasoulpour
R J
RJ
Yin
L
L
Hubbard
A K
AK
Rosenberg
D W
DW
Giardina
C
C
D000107:Acetylation; D002087:Butyrates / Q000494:pharmacology*; D002460:Cell Line; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D016207:Cytokines / Q000502:physiology; D019281:Dimerization; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*
D002087:Butyrates; D016207:Cytokines; D016328:NF-kappa B