Tumor necrosis factor-α and interferon-γ increase PepT1 expression and activity in the human colon carcinoma cell line Caco-2/bbe and in mouse intestine
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- Vavricka, S.R., Musch, M.W., Fujiya, M. et al. Pflugers Arch - Eur J Physiol (2006) 452: 71. doi:10.1007/s00424-005-0007-8
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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)-1β, IL-2, IL-8, IL-10, tumor necrosis factor-α, (TNF-α) and interferon-γ (IFN-γ ) up-regulate PepT1 activity and expression. Uptake of the PepT1 substrate glycylsarcosine [3H]-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-α and IFN-γ 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-α and IFN-γ, but not IL-1β, 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-α nor IFN-γ increased PepT1 mRNA expression in any segment of the intestine, treatment with IL-1β 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-α or IFN-γ may play a role in activating host responses in involved colon.