A major mechanism for apical
peptide absorption by small intestine is via the
proton-coupled transporter PepT1. PepT1 is expressed at a high level in proximal small intestine, but it is not expressed in the healthy colon. However, in chronic states of intestinal
inflammation, such as in
Crohn's disease and
ulcerative colitis, PepT1 expression in colonic epithelia is increased, serving as a pathway for entry of bacteria-derived molecules such as
muramyl dipeptide (MDP) and
fMet-Leu-Phe (fMLP). As little is known of how
inflammation induces PepT1, we investigated whether or not inflammatory
cytokines and mediators such as
interleukins (IL)-1beta,
IL-2,
IL-8,
IL-10,
tumor necrosis factor-alpha, (
TNF-alpha) and
interferon-gamma (IFN-gamma ) up-regulate PepT1 activity and expression. Uptake of the PepT1 substrate
glycylsarcosine [(3)H]-
Gly-Sar was studied in vitro in the human colon
carcinoma cell line Caco2/bbe monolayers as well as in vivo in mice injected with
cytokines.
TNF-alpha and IFN-gamma increased the activity, and total and apical
membrane protein expression of
PepT1 protein in a concentration- and time-dependent fashion. No changes in PepT1
mRNA were observed, suggesting post-transcriptional regulation. All three
cytokines increased
PepT1 protein expression in mouse proximal and distal colon but not in jejunum or ileum.
TNF-alpha and IFN-gamma, but not IL-1beta, increased
Gly-Sar uptake in mouse proximal and distal colon; however, no changes were observed in the small intestine with any
cytokine treatment. Whereas neither
TNF-alpha nor IFN-gamma increased PepT1
mRNA expression in any segment of the intestine, treatment with IL-1beta increased PepT1
mRNA expression in mouse proximal and distal colon and decreased PepT1
mRNA expression in jejunum and ileum. Since PepT1 transports bacteria-derived
peptides, the up-regulation of
protein expression and activity observed
after treatment with
TNF-alpha or IFN-gamma may play a role in activating host responses in involved colon.