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G protein-coupled receptor kinase 6 controls chronicity and severity of DSS-induced colitis in mice
  1. Niels Eijkelkamp (n.eijkelkamp{at}umcutrecht.nl)
  1. Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Netherlands
    1. Cobi J Heijnen (c.heijnen{at}umcutrecht.nl)
    1. Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Netherlands
      1. Ayscha Lucas
      1. Department of Medical Psychology, University Hospital of Essen, University of Duisburg-Essen, Germany
        1. Richard T Premont
        1. Department of Medicine, Duke University Medical Center, Durham, United States
          1. Sigrid Elsenbruch
          1. Department of Medical Psychology, University Hospital of Essen, University of Duisburg-Essen, Germany
            1. Manfred Schedlowski
            1. Psychology & Behavioural Immunobiology Division, Swiss Federal Institute of Technology, Zürich, Switzerland
              1. Annemieke Kavelaars (a.kavelaars{at}umcutrecht.nl)
              1. Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Netherlands

                Abstract

                Background: Infiltration of inflammatory cells into the colon plays an important role in the onset and course of inflammatory bowel disease. G protein receptor kinase 6 (GRK6) is an intracellular kinase that regulates the sensitivity of certain G protein-coupled receptors (GPCRs), including GPCRs involved in inflammatory cell migration. Therefore, we hypothesized that GRK6 plays a role in determining the course of inflammation. To test this hypothesis, we analyzed the role of GRK6 in the course of dextran sodium sulphate (DSS)-colitis.

                Methods: Colitis was induced by administering 1% DSS in drinking water to GRK6-/-, GRK6+/- and wild type (WT) mice for 6 days. Severity of colitis was assessed by clinical signs, colon length and histology. Moreover, KC levels, granulocyte infiltration, IL-1β, CD4, CD8 and Foxp3 expression in the colon was determined. In addition, regulatory T-cell function in WT and GRK6-/- was analysed. The chemotactic response of granulocytes towards colon culture supernatants was assessed with a transendothelial migration assay.

                Results: Severity of colitis was increased in GRK6-/- and GRK6+/- mice and was accompanied by increased KC levels and increased granulocyte infiltration. Moreover, the chemotactic response of GRK6-/- granulocytes towards supernatants of colon cultures was enhanced. Interestingly, WT mice completely recovered from colitis, whereas GRK6-/- and GRK6+/- mice developed chronic colitis, which was accompanied by increased IL-1β and CD4 expression and decreased FOXP3 expression. Moreover, regulatory T-cell function was impaired in GRK6-/- mice.

                Conclusion: The intracellular level of GRK6 is an important factor in determining the onset, severity and chronicity of DSS colitis.

                • DSS colitis
                • G protein-coupled receptor kinase 6
                • GRK6 knockout mice
                • chronic colitis
                • regulatory T-cells

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