Involvement of different nuclear hormone receptors in butyrate-mediated inhibition of inducible NF kappa B signalling.
BACKGROUND
NF kappa B plays a major role in the control of immune responses and inflammation. Recently, butyrate has not only been demonstrated to suppress NF kappa B activation in colorectal cancer cells, but also to modulate the activity and expression of the Peroxisome-Proliferator-Activated-Receptor gamma (PPAR gamma) and the vitamin D receptor (VDR). Therefore, we investigated a putative involvement of both receptors in butyrate-mediated inhibition of inducible NF kappa B signalling.


RESULTS
Treatment of HT-29 cells with butyrate attenuated basal p50 as well as TNFalpha- and LPS-induced p50 and p65 NF kappa B dimer activity in the nucleus as measured by transcription factor assay. Cytosolic expression of I kappa B alpha protein was reduced by butyrate, and TNFalpha but not by LPS. Challenge of cells with the VDR antagonist ZK191732 up-regulated basal NF kappa B activity by decreasing I kappa B alpha simultaneously, while basal signalling was not influenced by the PPAR gamma inhibitor GW9662. Pre-treatment with ZK191732 reduced the inhibitory effect of butyrate on NF kappa B activation caused by TNFalpha whereas no activation was noted in transfected dominant-negative PPAR gamma mutant vector cells. Adversely, the inhibitory effect of butyrate on NF kappa B activity induced by LPS was almost reversed in dominant-negative PPAR gamma mutant cells while pre-incubation of ZK191732 did not affect butyrate-mediated attenuation of LPS-induced NF kappa B signalling.


CONCLUSIONS
These findings provide evidence for the involvement of the nuclear hormone receptors PPAR gamma and VDR in butyrate-mediated inhibition of inducible NF kappa B activation dependent on the stimulated signalling pathway. Moreover, VDR appears to play an inhibitory role in the regulation of basal NF kappa B signalling.
Schwab
Markus
M
First Department of Medicine-ZAFES, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Reynders
Veerle
V
Loitsch
Stefan
S
Steinhilber
Dieter
D
Stein
Jürgen
J
Schröder
Oliver
O
D002087:Butyrates / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D019073:HT29 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D002087:Butyrates; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D047495:PPAR gamma; D018167:Receptors, Calcitriol; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA