title: A novel role for interleukin-27 (IL-27) as mediator of intestinal epithelial barrier protection mediated via differential signal transducer and activator of transcription (STAT) protein signaling and induction of antibacterial and anti-inflammatory proteins.
abstract: The role of the Th17 cell inhibiting cytokine IL-27 in the pathogenesis of inflammatory bowel disease is contradictory. Its effects on the intestinal barrier have so far not been investigated, which was the aim of this study. We show that intestinal epithelial cells (IEC) express both IL-27 receptor subunits IL-27RA and gp130. The IL-27 receptor expression is up-regulated in intestinal inflammation and during bacterial infection. IL-27 activates ERK and p38 MAPKs as well as Akt, STAT1, STAT3, and STAT6 in IEC. IL-27 significantly enhances cell proliferation and IEC restitution. These functions of IL-27 are dependent on the activation of STAT3 and STAT6 signaling pathways. As analyzed by microarray, IL-27 modulates the expression of 428 target genes in IEC (316 up and 112 down; p<0.05). IL-27 as well as its main target genes are up-regulated in colonic tissue and IEC isolated from mice with dextran sulfate sodium (DSS)-induced colitis. The IL-27-induced expression of the anti-bacterial gene deleted in malignant brain tumor 1 (DMBT1) is mediated by p38 and STAT3 signaling, whereas the activation of the anti-inflammatory and anti-bacterial gene indoleamine 2,3-dioxygenase (IDO1) is dependent on STAT1 signal transduction. IL-27-induced indoleamine 2,3-dioxygenase enzymatic activity leads to growth inhibition of intestinal bacteria by causing local tryptophan depletion. For the first time, we characterize IL-27 as a mediator of intestinal epithelial barrier protection mediated via transcriptional activation of anti-inflammatory and antibacterial target genes.
authors: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University, Munich, 81377, Germany; Department of Preventive Dentistry and Periodontology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors: Julia
authors: J
authors: Diegelmann
authors: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University, Munich, 81377, Germany; Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Torsten
authors: T
authors: Olszak
authors: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University, Munich, 81377, Germany.
authors: Burkhard
authors: B
authors: Göke
authors: Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Richard S
authors: RS
authors: Blumberg
authors: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University, Munich, 81377, Germany. Electronic address: stephan.brand@med.uni-muenchen.de.
authors: Stephan
authors: S
authors: Brand
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000235:genetics; D003424:Crohn Disease / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D016264:Dextran Sulfate / Q000009:adverse effects; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D015203:Reproducibility of Results; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C108174:DMBT1 protein, human; D004268:DNA-Binding Proteins; C114202:Dmbt1 protein, mouse; C112441:IL27RA protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020381:Interleukin-17; D009077:Mucins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D050791:STAT Transcription Factors; D025521:Tumor Suppressor Proteins; D016264:Dextran Sulfate; D048051:p38 Mitogen-Activated Protein Kinases