G protein-coupled receptor kinase 6 controls chronicily and severity of dextran sodium sulphate-induced colitis in mice

Eijkelkamp, Niels; Heijnen, Cobi J.; Lucas, Ayscha; Premont, Richard T.; Elsenbruch, Sigrid; Schedlowski, Manfred; Kavelaars, Annemieke
June 2007
Gut;Jun2007, Vol. 56 Issue 6, p847
Academic Journal
Background: Infiltration of inflammatory cells into the colon piays an important role in the onset and course of inflammatory bowel disease. G-protein-coupled receptor kinase 6 (GRK6) is an intracellular kinase that regulates the sensitivity of certain G-protein-coupled receptors, including those involved in the migration of inflammatory cells. Therefore, it is hypothesised that GRK6 plays a role in determining the course of inflammation. Aim: To analyse the role of GRK6 in the course of dextran sodium sulphate (DSS)-induced colitis. Methods: Colitis was induced by administering 1% DSS in drinking water to GRK6-/-, GRK6+/- and wild-type (WT) mice for 6 days. The severity of colitis was assessed on the basis of clinical signs, colon length and histology. Moreover, keratinocyte-derived chemokine (KC) levels, granulocyte infiltration, interleukin 1β (IL1 β), CD4, CD8 and forkhead box protein P3 (FoxP3) expression in the colon were determined. In addition, regulatory T cell function in WT and GRK6-/- mice was analysed. The chemotactic response of granulocytes to colon culture supernatants was assessed using a transendothelial migration assay. Results: The severity of colitis was increased in GRK6-/- and GRK6+/-1 mice and was accompanied by increased KC levels and increased granulocyte infiltration. Moreover, the chemotactic response of GRK6-/- granulocytes to supernatants of colon cultures was enhanced. Interestingly, the WT mice completely recovered from colitis, whereas the GRK6-/- and GRK6+/- mice developed chronic colitis, which was accompanied by increased IL1 β and CD4 expression and decreased FoxP3 expression. Moreover, regulatory T cell function was impaired in the GRK6-/- mice. Conclusions: The intracellular level of GRK6 is an important factor in determining the onset, severity and chronicity of DSS-induced colitis.


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