The Experts below are selected from a list of 201759 Experts worldwide ranked by ideXlab platform
Brent D Polk - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Biological Chemistry, 2013Co-Authors: Fang Yan, Liping Liu, Peter J Dempsey, Yu Hwai Tsai, Elaine W Raines, Carole L Wilson, Hailong Cao, Zheng Cao, Linshu Liu, Brent D PolkAbstract:p40, a Lactobacillus rhamnosus GG (LGG)-derived Soluble Protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic 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 transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17(-/-) MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17(-/-) MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived Soluble Protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR.
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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
Journal of Biological Chemistry, 2013Co-Authors: Fang Yan, Liping Liu, Peter J Dempsey, Yu Hwai Tsai, Elaine W Raines, Carole L Wilson, Hailong Cao, Zheng Cao, Linshu Liu, Brent D PolkAbstract:p40, a Lactobacillus rhamnosus GG (LGG)-derived Soluble Protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic 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 transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17−/− MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17−/− MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived Soluble Protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR. Background: p40 is a Lactobacillus rhamnosus GG-derived Protein. Results: p40 stimulates ADAM17 activation and HB-EGF release, which is required for EGF receptor transactivation, prevention of apoptosis, and preservation of barrier function in intestinal epithelial cells. Conclusion: p40 transactivates the EGF receptor through ADAM17-mediated HB-EGF release in intestinal epithelial cells. Significance: These results define a mechanism of p40 in modulating intestinal epithelial cell homeostasis.
Fang Yan - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Biological Chemistry, 2013Co-Authors: Fang Yan, Liping Liu, Peter J Dempsey, Yu Hwai Tsai, Elaine W Raines, Carole L Wilson, Hailong Cao, Zheng Cao, Linshu Liu, Brent D PolkAbstract:p40, a Lactobacillus rhamnosus GG (LGG)-derived Soluble Protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic 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 transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17(-/-) MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17(-/-) MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived Soluble Protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR.
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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
Journal of Biological Chemistry, 2013Co-Authors: Fang Yan, Liping Liu, Peter J Dempsey, Yu Hwai Tsai, Elaine W Raines, Carole L Wilson, Hailong Cao, Zheng Cao, Linshu Liu, Brent D PolkAbstract:p40, a Lactobacillus rhamnosus GG (LGG)-derived Soluble Protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic 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 transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17−/− MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17−/− MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived Soluble Protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR. Background: p40 is a Lactobacillus rhamnosus GG-derived Protein. Results: p40 stimulates ADAM17 activation and HB-EGF release, which is required for EGF receptor transactivation, prevention of apoptosis, and preservation of barrier function in intestinal epithelial cells. Conclusion: p40 transactivates the EGF receptor through ADAM17-mediated HB-EGF release in intestinal epithelial cells. Significance: These results define a mechanism of p40 in modulating intestinal epithelial cell homeostasis.
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Colon-specific delivery of a probiotic-derived Soluble Protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism
Journal of Clinical Investigation, 2011Co-Authors: Fang Yan, Linshu Liu, Hanwei Cao, Timothy L. Cover, M. Kay Washington, Yan Shi, Rupesh Chaturvedi, Richard M. Peek, Keith T. Wilson, D. Brent PolkAbstract:Probiotic bacteria can potentially have beneficial effects on the clinical course of several intestinal disorders, but our understanding of probiotic action is limited. We have identified a probiotic bacteria-derived Soluble Protein, p40, from Lactobacillus rhamnosus GG (LGG), which prevents cytokine-induced apoptosis in intestinal epithelial cells. In the current study, we analyzed the mechanisms by which p40 regulates cellular responses in intestinal epithelial cells and p40's effects on experimental colitis using mouse models. We show that the recombinant p40 Protein activated EGFR, leading to Akt activation. Activation of EGFR by p40 was required for inhibition of cytokine-induced apoptosis in intestinal epithelial cells in vitro and ex vivo. Furthermore, we developed a pectin/zein hydrogel bead system to specifically deliver p40 to the mouse colon, which activated EGFR in colon epithelial cells. Administration of p40-containing beads reduced intestinal epithelial apoptosis and disruption of barrier function in the colon epithelium in an EGFR-dependent manner, thereby preventing and treating DSS-induced intestinal injury and acute colitis. Furthermore, p40 activation of EGFR was required for ameliorating colon epithelial cell apoptosis and chronic inflammation in oxazolone-induced colitis. These data define what we believe to be a previously unrecognized mechanism of probiotic-derived Soluble Proteins in protecting the intestine from injury and inflammation.
Linshu Liu - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Biological Chemistry, 2013Co-Authors: Fang Yan, Liping Liu, Peter J Dempsey, Yu Hwai Tsai, Elaine W Raines, Carole L Wilson, Hailong Cao, Zheng Cao, Linshu Liu, Brent D PolkAbstract:p40, a Lactobacillus rhamnosus GG (LGG)-derived Soluble Protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic 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 transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17(-/-) MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17(-/-) MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived Soluble Protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR.
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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
Journal of Biological Chemistry, 2013Co-Authors: Fang Yan, Liping Liu, Peter J Dempsey, Yu Hwai Tsai, Elaine W Raines, Carole L Wilson, Hailong Cao, Zheng Cao, Linshu Liu, Brent D PolkAbstract:p40, a Lactobacillus rhamnosus GG (LGG)-derived Soluble Protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic 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 transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17−/− MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17−/− MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived Soluble Protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR. Background: p40 is a Lactobacillus rhamnosus GG-derived Protein. Results: p40 stimulates ADAM17 activation and HB-EGF release, which is required for EGF receptor transactivation, prevention of apoptosis, and preservation of barrier function in intestinal epithelial cells. Conclusion: p40 transactivates the EGF receptor through ADAM17-mediated HB-EGF release in intestinal epithelial cells. Significance: These results define a mechanism of p40 in modulating intestinal epithelial cell homeostasis.
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Colon-specific delivery of a probiotic-derived Soluble Protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism
Journal of Clinical Investigation, 2011Co-Authors: Fang Yan, Linshu Liu, Hanwei Cao, Timothy L. Cover, M. Kay Washington, Yan Shi, Rupesh Chaturvedi, Richard M. Peek, Keith T. Wilson, D. Brent PolkAbstract:Probiotic bacteria can potentially have beneficial effects on the clinical course of several intestinal disorders, but our understanding of probiotic action is limited. We have identified a probiotic bacteria-derived Soluble Protein, p40, from Lactobacillus rhamnosus GG (LGG), which prevents cytokine-induced apoptosis in intestinal epithelial cells. In the current study, we analyzed the mechanisms by which p40 regulates cellular responses in intestinal epithelial cells and p40's effects on experimental colitis using mouse models. We show that the recombinant p40 Protein activated EGFR, leading to Akt activation. Activation of EGFR by p40 was required for inhibition of cytokine-induced apoptosis in intestinal epithelial cells in vitro and ex vivo. Furthermore, we developed a pectin/zein hydrogel bead system to specifically deliver p40 to the mouse colon, which activated EGFR in colon epithelial cells. Administration of p40-containing beads reduced intestinal epithelial apoptosis and disruption of barrier function in the colon epithelium in an EGFR-dependent manner, thereby preventing and treating DSS-induced intestinal injury and acute colitis. Furthermore, p40 activation of EGFR was required for ameliorating colon epithelial cell apoptosis and chronic inflammation in oxazolone-induced colitis. These data define what we believe to be a previously unrecognized mechanism of probiotic-derived Soluble Proteins in protecting the intestine from injury and inflammation.
Carole L Wilson - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Biological Chemistry, 2013Co-Authors: Fang Yan, Liping Liu, Peter J Dempsey, Yu Hwai Tsai, Elaine W Raines, Carole L Wilson, Hailong Cao, Zheng Cao, Linshu Liu, Brent D PolkAbstract:p40, a Lactobacillus rhamnosus GG (LGG)-derived Soluble Protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic 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 transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17(-/-) MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17(-/-) MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived Soluble Protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR.
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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
Journal of Biological Chemistry, 2013Co-Authors: Fang Yan, Liping Liu, Peter J Dempsey, Yu Hwai Tsai, Elaine W Raines, Carole L Wilson, Hailong Cao, Zheng Cao, Linshu Liu, Brent D PolkAbstract:p40, a Lactobacillus rhamnosus GG (LGG)-derived Soluble Protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic 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 transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17−/− MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17−/− MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived Soluble Protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR. Background: p40 is a Lactobacillus rhamnosus GG-derived Protein. Results: p40 stimulates ADAM17 activation and HB-EGF release, which is required for EGF receptor transactivation, prevention of apoptosis, and preservation of barrier function in intestinal epithelial cells. Conclusion: p40 transactivates the EGF receptor through ADAM17-mediated HB-EGF release in intestinal epithelial cells. Significance: These results define a mechanism of p40 in modulating intestinal epithelial cell homeostasis.
Liping Liu - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Biological Chemistry, 2013Co-Authors: Fang Yan, Liping Liu, Peter J Dempsey, Yu Hwai Tsai, Elaine W Raines, Carole L Wilson, Hailong Cao, Zheng Cao, Linshu Liu, Brent D PolkAbstract:p40, a Lactobacillus rhamnosus GG (LGG)-derived Soluble Protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic 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 transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17(-/-) MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17(-/-) MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived Soluble Protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR.
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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
Journal of Biological Chemistry, 2013Co-Authors: Fang Yan, Liping Liu, Peter J Dempsey, Yu Hwai Tsai, Elaine W Raines, Carole L Wilson, Hailong Cao, Zheng Cao, Linshu Liu, Brent D PolkAbstract:p40, a Lactobacillus rhamnosus GG (LGG)-derived Soluble Protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic 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 transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17−/− MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17−/− MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived Soluble Protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR. Background: p40 is a Lactobacillus rhamnosus GG-derived Protein. Results: p40 stimulates ADAM17 activation and HB-EGF release, which is required for EGF receptor transactivation, prevention of apoptosis, and preservation of barrier function in intestinal epithelial cells. Conclusion: p40 transactivates the EGF receptor through ADAM17-mediated HB-EGF release in intestinal epithelial cells. Significance: These results define a mechanism of p40 in modulating intestinal epithelial cell homeostasis.
