Gregor Paul

Medical University of Vienna, Wien, Vienna, Austria

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Publications (2)2.73 Total impact

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    ABSTRACT: The mucosal immune response in the setting of intestinal inflammation contributes to colorectal cancer (CRC). IL-10 signaling has central role in gut homeostasis and is impaired in inflammatory bowel disease (IBD). Out of two IL-10 receptor subunits, IL-10R1 and IL-10R2, the latter is shared among the IL-10 family of cytokines and activates STAT signaling. STAT3 is oncogenic in CRC, however, knowledge about IL-10 signaling upstream of STAT3 in CRC is lacking. Here, expression of IL-10 signaling genes was examined in matched pairs from normal and tumor tissue from CRC patients showing overexpression (mRNA, protein) of IL-10R2 and STAT3 but not IL-10R1. IL-10R2 over-expression was related to microsatellite- stability. Transient overexpression of IL-10R2 in HT29 cells increased proliferation upon ligand activation (IL-10, IL-22). IL-22 and not IL-10 phosphorylated STAT3 along with increased phosphorylation of AKT and ERK. A significantly higher expression of IL-22R1 and IL-10R2 was also confirmed in separate cohort of CRC samples. IL-22 expression was elevated in gut mucosa from patients with IBD and colitis-associated cancer which also exhibited increased expression of IL-22R1 but not its co-receptor IL-10R2. Overall, these data indicate that overexpression of IL-10R2 and STAT3 contribute to colorectal carcinogenesis in microsatellite stable tumors through IL-22/STAT3 signaling. Copyright © 2015, American Association for Cancer Research.
    Full-text · Article · Jun 2015
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    Gregor Paul · Vineeta Khare · Christoph Gasche
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    ABSTRACT: Interleukin-10 is a pleiotropic cytokine, whose main function is limitation and ultimately termination of immune responses. This is especially true for environmental interfaces such as the gastrointestinal tract. IL-10 acts as a key mediator for maintaining gut homeostasis. IL-10 knockout mice are well established as a genetic model for inflammatory bowel disease (IBD), and sequence variants in the IL-10 locus contribute to ulcerative colitis (UC). This review covers the significance of IL-10 signalling in the intestinal immune response both in health and disease. It explains the biological role of IL-10, its deregulation in IBD and its contribution to intestinal inflammation via endoplasmic reticulum stress response. Many IBD susceptibility genes have been discovered in the past years, linking fundamental biological systems, like innate and adaptive immunity, stress responses, autophagy and mucosal barrier to the pathogenesis of Crohn's disease (CD) and UC. IL-10 has long been known for its substantial role in regulating gut immunity, but its contribution to IBD was somewhat elusive. A recent study identified mutations in either IL-10 receptor subunits that are associated with early-onset enterocolitis, a severe phenotype of IBD. Other than genetic variants of IL-10 receptors, IL-10 and STAT3 genes are also associated with IBD, emphasizing the involvement of the IL-10 signalling cascade in the pathogenesis of CD and UC.   The discovery of inherited deregulations in the IL-10 signalling cascade is not only considered the missing link between IL-10 and intestinal homeostasis, but also demonstrates how findings made in animal models help explaining human disease.
    Full-text · Article · Jun 2011 · European Journal of Clinical Investigation