Submitted March 28, 2008
Accepted June 22, 2008
A role for multidrug resistance protein 4 (MRP4; ABCC4) in human dendritic cell migration
Rieneke van de Ven, George L Scheffer, Anneke W Reurs, Jelle J Lindenberg, Ruud Oerlemans, Gerrit Jansen, Jean-Pierre Gillet, Joel N Glasgow, Alexander Pereboev, David T Curiel, Rik J Scheper, and Tanja D de Gruijl*
Department of Pathology, VU University Medical Center, Amsterdam, Netherlands
Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands
Department of Rheumatology, VU University Medical Center, Amsterdam, Netherlands
Department of Biology, University of Namur, Namur, Belgium
Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
Division of Human Gene Therapy (DHGT), University of Alabama at Birmingham, Birmingham, Alabama, United States
* Corresponding author; email: td.degruijl{at}vumc.nl.
The capacity of dendritic cells (DC) to migrate from peripheral organs to lymph nodes (LN) is important in the initiation of a T cell-mediated immune response. Previously it was shown that the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp; ABCB1) and the multidrug resistance protein 1 (MRP1; ABCC1) play a role in both human and murine DC migration. Here we show that a more recently discovered family-member, MRP4 (ABCC4) is expressed on both epidermal and dermal human skin DC and contributes to the migratory capacity of DC. Pharmacological inhibition of MRP4 activity or down-regulation through RNAi in DC resulted in reduced migration of DC from human skin explants and of in vitro generated Langerhans cells. The responsible MRP4 substrate remains to be identified as exogenous addition of MRP4's known substrates PGE2, leukotriene B4 and D4 or cyclic nucleotides (all previously implicated in DC migration) could not restore migration. This notwithstanding, our data show that MRP4 is an important protein, significantly contributing to human DC migration towards the draining lymph nodes, and thereby relevant for the initiation of an immune response and a possible target for immunotherapy.
