P075. Oncostatin M promotes STAT3-dependent intestinal epithelial cell proliferation and MEK-1-dependent intestinal wound healing
F. Beigel1, C. Probst2, M. Friedrich2, B. Göke2, J. Diegelmann2, S. Brand2
1University Hospital Munich Grosshadern, Medizinische Klinik und Poliklinik 2, Munich, Germany; 2University Hospital Munich Grosshadern, LMU Munich, Munich, Germany
Background: Oncostatin M (OSM), a member of the IL‑6 family, is produced by activated T cells, monocytes, and dendritic cells and signals through two distinct receptor complexes consisting of OSMR-beta and LIFR (type I) or OSMR-beta and gp130 (type II), respectively. The aim of this study was to analyze OSM receptor expression, signal transduction and specific biological functions of this cytokine in intestinal epithelial cells (IEC).
Methods: Receptor expression experiments were carried out by semiquantitative PCR. Signal transduction was analyzed by Western blot experiments. Expression studies were performed by microarray analysis (Agilent Technologies, Santa Clara, CA, U.S.A.) and quantitative PCR (qPCR). Signal transduction was analyzed by Western blot experiments. IEC restitution was studied in proliferation assays (WST‑1) and wound healing experiments.
Results: The IEC lines Caco‑2, DLD‑1, SW480, HCT116 and HT-29 express mRNA for the OSM receptor subunits OSMR-beta, LIFR and gp130. OSM binding to its receptor complex activates the MAP kinases ERK-1/2 and SAPK/JNK-1/2, the PI3-kinase Akt, and STAT1 and STAT3. OSM significantly enhanced MEK-1-dependent IEC wound healing (p = 0.0002) and increased STAT3- and MEK‑1 kinase-dependent IEC cell proliferation (p = 0.04). As revealed by microarray analysis, 79 genes were significantly up-regulated by OSM (adj.-p < 0.05, >2-fold increase). Panther software analysis showed several genes involved in immunity and defense (p = 2.1×10−7) and apoptosis (p = 3.7×10−4) among the most up-regulated genes, including SERPIN gene family members (SERPINB4: 39.4-fold, SERPINB3: 36.3-fold, SERPINA3: 9.2-fold; all p < 0.01). In contrast, only a limited number of genes were significantly down-regulated (n = 15; adj.-p < 0.05).
Conclusions: IEC express functional receptors for OSM which promotes intestinal barrier functions via IEC restitution and up-regulation of genes involved in autoimmunity and defense and apoptosis, suggesting an important function in intestinal inflammation and wound healing.