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A lactobacillus rhamnosus GG-derived soluble protein, p40, stimulates ligand release from intestinal epithelial cells to transactivate epidermal growth factor receptor

Fang Yan, Liping Liu, Peter J. Dempsey, Yu-Hwai Tsai, Elaine W. Raines, Carole L. Wilson, Hailong Cao, Zheng Cao, LinShu Liu, D. Brent Polk
Journal of biological chemistry 2014 v.288 no.42 pp. 30742-30751
Lactobacillus rhamnosus, adults, apoptosis, bacterial proteins, blood, catalytic activity, colitis, colon, epidermal growth factor receptors, epithelial cells, heparin, homeostasis, humans, hydrocolloids, intestinal mucosa, mice, pectins, preserves, small interfering RNA, tight junctions, transcriptional activation, transfection, transforming growth factors, zein
Protein p40, a Lactobacillus rhamnosus GG (LGG)-derived soluble protein, ameliorates intestinal injury and colitis, reduces apoptosis and preserves barrier function by activation of EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study was to determine the mechanisms by which p40 transactivates EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in both young adult mouse colon (YAMC) epithelial cells and human colon epithelial cell line, T84 cells. p40 up-regulates a disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) catalytic activity and broad-spectrum metalloproteinase inhibitors block EGFR activation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17-/- MCE) cells, p40 activation of EGFR is blocked, but can be rescued by re-expression with wt ADAM17. Furthermore, p40 stimulates heparin binding (HB)-EGF release, but not transforming growth factor (TGF)a or amphiregulin in YAMC cells and ADAM17-/- MCE cells overexpressing wt ADAM17. Knock-down of HBEGF expression by siRNA transfection suppressed p40’s effects on activation of EGFR and Akt, prevented apoptosis, and preserved tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo were examined after administration of p40 containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in the colon epithelial cells and increases HB-EGF level in blood from wt mice, but not from conditional intestinal epithelial cell (IEC)-specific ADAM17-deficient mice. Thus, these data define a mechanism of probiotic-derived soluble proteins in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR.