Oncostatin M mediates STAT3-dependent intestinal epithelial restitution via increased cell proliferation, decreased apoptosis and upregulation of SERPIN family members.
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-β 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-β, 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 = 2.1 × 10(-7)), "apoptosis" (p = 3.7 × 10(-4)) and "JAK/STAT cascade" (p = 3.4 × 10(-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 = 3.9 × 10(-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.
Department of Medicine II, University-Hospital Munich-Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany.
Florian
F
Beigel
Department of Medicine II, University-Hospital Munich-Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany; Clinic for Preventive Dentistry and Parodontology, Ludwig-Maximilians-University Munich, Munich, Germany.
Matthias
M
Friedrich
Department of Medicine II, University-Hospital Munich-Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany.
Corina
C
Probst
Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany.
Karl
K
Sotlar
Department of Medicine II, University-Hospital Munich-Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany.
Burkhard
B
Göke
Department of Medicine II, University-Hospital Munich-Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany; Clinic for Preventive Dentistry and Parodontology, Ludwig-Maximilians-University Munich, Munich, Germany.
Julia
J
Diegelmann
Department of Medicine II, University-Hospital Munich-Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany.
Stephan
S
Brand
D017209:Apoptosis; D018938:Caco-2 Cells; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053683:Oncostatin M / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015843:Serpins / Q000096:biosynthesis*; D015854:Up-Regulation; D014945:Wound Healing
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015843:Serpins; D053683:Oncostatin M