title: An LGG-derived protein promotes IgA production through upregulation of APRIL expression in intestinal epithelial cells.
abstract: p40, a Lactobacillus rhamnosus GG (LGG)-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells, leading to amelioration of intestinal injury and inflammation. To elucidate mechanisms by which p40 regulates mucosal immunity to prevent inflammation, this study aimed to determine the effects and mechanisms of p40 on regulation of a proliferation-inducing ligand (APRIL) expression in intestinal epithelial cells for promoting immunoglobulin A (IgA) production. p40 upregulated April gene expression and protein production in mouse small intestine epithelial (MSIE) cells, which were inhibited by blocking EGFR expression and kinase activity. Enteroids from Egfrfl/fl, but not Egfrfl/fl-Vil-Cre mice with EGFR specifically deleted in intestinal epithelial cells, exhibited increased April gene expression by p40 treatment. p40-conditioned media from MSIE cells increased B-cell class switching to IgA+cells and IgA production, which was suppressed by APRIL receptor-neutralizing antibodies. Treatment of B cells with p40 did not show any effects on IgA production. p40 treatment increased April gene expression and protein production in small intestinal epithelial cells, fecal IgA levels, IgA+B220+, IgA+CD19+, and IgA+plasma cells in lamina propria of Egfrfl/fl, but not of Egfrfl/fl-Vil-Cre, mice. Thus p40 upregulates EGFR-dependent APRIL production in intestinal epithelial cells, which may contribute to promoting IgA production.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Immunology and Biotherapy Center, National Clinical Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Endocrinology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Moore
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: X
authors.initials: X
authors.lastname: Shen
authors.affiliation: Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Peek
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Acra
authors.affiliation: Department of Immunology and Biotherapy Center, National Clinical Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Immunology and Biotherapy Center, National Clinical Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Pediatrics, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA.|Department of Biochemistry and Molecular Biology, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA.|The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Polk
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: F
authors.initials: F
authors.lastname: Yan
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D007070:Immunoglobulin A / Q000378:metabolism; D007421:Intestine, Small / Q000473:pathology*; D052201:Lacticaseibacillus rhamnosus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics; D015533:Transcriptional Activation; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D001426:Bacterial Proteins; D007070:Immunoglobulin A; D034741:RNA, Small Interfering; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C560306:p40 protein, Lactobacillus rhamnosus; C541485:EGFR protein, mouse; D066246:ErbB Receptors