Post-translational and cell type-specific regulation of CXCR4 expression by cytokines

Eur J Immunol. 2003 Nov;33(11):3028-37. doi: 10.1002/eji.200324163.


We have investigated the regulation and function of the chemokine receptor CXCR4 on neutrophils. CXCR4 is hardly detectable on neutrophils in the peripheral blood. However, overnight culture strongly up-regulates CXCR4 expression on the cell surface. The functional activity of CXCR4 on cultured neutrophils was confirmed by stromal cell-derived factor (SDF)-induced migration and up-regulation of the integrins CD11b and CD11c. CXCR4 surface expression on neutrophils but not on lymphocytes and monocytes is rapidly down-regulated after stimulation with TNF-alpha and IFN-gamma, resulting in significantly decreased SDF-induced functional responses of neutrophils. In contrast to surface expression, CXCR4 mRNA expression was several-fold increased in cytokine-stimulated neutrophils, suggesting a post-translational regulation. By confocal microscopy we demonstrate that CXCR4 is internalized after stimulation with TNF-alpha and IFN-gamma. Tauhe down-modulation of CXCR4 surface expression in response to TNF-alpha and IFN-gamma was fully reversible after cytokine removal. Further, CXCR4 down-modulation could be completely blocked by hypertonic sucrose and significantly reduced by chlorpromazine indicating the involvement of clathrin-coated pits. Internalization of CXCR4 by cytokines in a cell type-specific manner is a novel and functionally important mechanism of chemokine receptor regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Movement / physiology
  • Chemokine CXCL12
  • Chemokines, CXC / metabolism
  • Coated Pits, Cell-Membrane / metabolism
  • Cytokines / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Integrins / metabolism
  • Interferon-gamma / metabolism
  • Neutrophils / metabolism
  • Protein Processing, Post-Translational*
  • Receptors, CXCR4 / biosynthesis
  • Receptors, CXCR4 / genetics*
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation


  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Cytokines
  • Integrins
  • Receptors, CXCR4
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma