Oncostatin M Mediates STAT3-Dependent Intestinal Epithelial Restitution via Increased Cell Proliferation, Decreased Apoptosis and Upregulation of SERPIN Family Members

被引:51
作者
Beigel, Florian [1 ]
Friedrich, Matthias [1 ,3 ]
Probst, Corina [1 ]
Sotlar, Karl [2 ]
Goeke, Burkhard [1 ]
Diegelmann, Julia [1 ,3 ]
Brand, Stephan [1 ]
机构
[1] Univ Munich, Univ Hosp Munich Grosshadern, Dept Med 2, Munich, Germany
[2] Univ Munich, Inst Pathol, D-80539 Munich, Germany
[3] Univ Munich, Clin Prevent Dent & Parodontol, Munich, Germany
关键词
CROHNS-DISEASE; PROTEIN-KINASE; GROWTH-FACTOR; SIGNALING PATHWAY; GENE-EXPRESSION; ACTIVATION; INTERLEUKIN-6; LYMPHOCYTES; FRACTALKINE; MIGRATION;
D O I
10.1371/journal.pone.0093498
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Objective: Oncostatin M (OSM) is produced by activated T cells, monocytes, and dendritic cells and signals through two distinct receptor complexes consisting of gp130 and LIFR (I) or OSMR-beta and gp130 (II), respectively. Aim of this study was to analyze the role of OSM in intestinal epithelial cells (IEC) and intestinal inflammation. Methods: OSM expression and OSM receptor distribution was analyzed by PCR and immunohistochemistry experiments, signal transduction by immunoblotting. Gene expression studies were performed by microarray analysis and RT-PCR. Apoptosis was measured by caspases-3/7 activity. IEC migration and proliferation was studied in wounding and water soluble tetrazolium assays. Results: The IEC lines Caco-2, DLD-1, SW480, HCT116 and HT-29 express mRNA for the OSM receptor subunits gp130 and OSMR-b, while only HCT116, HT-29 and DLD-1 cells express LIFR mRNA. OSM binding to its receptor complex activates STAT1, STAT3, ERK-1/2, SAPK/JNK-1/2, and Akt. Microarray analysis revealed 79 genes that were significantly up-regulated (adj.-p <= 0.05) by OSM in IEC. Most up-regulated genes belong to the functional categories "immunity and defense'' (p=2.1x10(-7)), "apoptosis'' (p=3.7x10(-4)) and "JAK/STAT cascade'' (p=3.4x10(-6)). Members of the SERPIN gene family were among the most strongly up-regulated genes. OSM significantly increased STAT3- and MEK1-dependent IEC cell proliferation (p < 0.05) and wound healing (p=3.9x10(-5)). OSM protein expression was increased in colonic biopsies of patients with active inflammatory bowel disease (IBD). Conclusions: OSM promotes STAT3-dependent intestinal epithelial cell proliferation and wound healing in vitro. Considering the increased OSM expression in colonic biopsy specimens of patients with active IBD, OSM upregulation may modulate a barrier-protective host response in intestinal inflammation. Further in vivo studies are warranted to elucidate the exact role of OSM in intestinal inflammation and the potential of OSM as a drug target in IBD.
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页数:15
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