Oncostatin M mediates STAT3-dependent intestinal epithelial restitution via increased cell proliferation, decreased apoptosis and upregulation of SERPIN family members.

Abstract

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.

• Authors: Florian Beigel, Matthias Friedrich, Corina Probst, Karl Sotlar, Burkhard Göke, Julia Diegelmann, Stephan Brand
• Journal: PloS one (PLoS One) Vol. 9 Issue 4 Pg. e93498 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24710357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• STAT3 Transcription Factor
• STAT3 protein, human
• Serpins
• Oncostatin M

Topics

• Apoptosis
• Caco-2 Cells
• Cell Proliferation
• Female
• Humans
• Inflammatory Bowel Diseases (metabolism, pathology)
• Intestinal Mucosa (metabolism, pathology)
• Male
• Oncostatin M (metabolism)
• STAT3 Transcription Factor (metabolism)
• Serpins (biosynthesis)
• Up-Regulation
• Wound Healing