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G protein-coupled receptor kinase 6 controls chronicity and severity of dextran sodium sulphate-induced colitis in mice
  1. Niels Eijkelkamp1,
  2. Cobi J Heijnen1,
  3. Ayscha Lucas2,
  4. Richard T Premont3,
  5. Sigrid Elsenbruch2,
  6. Manfred Schedlowski4,
  7. Annemieke Kavelaars1
  1. 1Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2Department of Medical Psychology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
  3. 3Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
  4. 4Division of Psychology and Behavioural Immunobiology, Swiss Federal Institute of Technology, ETH-Zürich, Switzerland
  1. Correspondence to:
    Dr A Kavelaars
    Laboratory for Psychoneuroimmunology, University Medical Center Utrecht, Lundlaan 6, Room KC 03.063.0, 3584 EA Utrecht, The Netherlands;a.kavelaars{at}umcutrecht.nl

Abstract

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 1β (IL1β), 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 IL1β 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.

  • ANOVA, analysis of variance
  • CCR, chemokine (CC motif) receptor
  • DAI, Disease Activity Index
  • DSS, dextran sodium sulphate
  • EPO, eosinophil peroxidase
  • FoxP3, forkhead box protein P3
  • GPCR, G-protein-coupled receptor
  • GRK, G-protein-coupled receptor kinase
  • IL, interleukin
  • KC, keratinocyte-derived chemokine
  • LTB4, leucotriene B4
  • MPO, myeloperoxidase
  • Treg, regulatory T cells
  • WT, wild type

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Footnotes

  • Published Online First 17 January 2007

  • Competing interests: None.

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