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


Journal Article

BACKGROUND: Infiltration of inflammatory cells into the colon plays 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 1beta (IL1beta), 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(+/-) 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 IL1beta 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.

Full Text

Cited Authors

  • Eijkelkamp, N; Heijnen, CJ; Lucas, A; Premont, RT; Elsenbruch, S; Schedlowski, M; Kavelaars, A

Published Date

  • June 2007

Published In

Volume / Issue

  • 56 / 6

Start / End Page

  • 847 - 854

PubMed ID

  • 17229795

Pubmed Central ID

  • 17229795

Electronic International Standard Serial Number (EISSN)

  • 1468-3288

International Standard Serial Number (ISSN)

  • 0017-5749

Digital Object Identifier (DOI)

  • 10.1136/gut.2006.107094


  • eng