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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