Differential regulation of chemokine CCL5 expression in monocytes/macrophages and renal cells by Y-box protein-1.
The Y-box protein-1 (YB-1) belongs to the family of cold shock proteins that have pleiotropic functions such as gene transcription, RNA splicing, and mRNA translation. YB-1 has a critical role in atherogenesis due to its regulatory effects on chemokine CCL5 (RANTES) gene transcription in vascular smooth muscle cells. Since CCL5 is a key mediator of kidney transplant rejection, we determined whether YB-1 is involved in allograft rejection by manipulating its expression. In human kidney biopsies, YB-1 transcripts were amplified 17-fold in acute and 21-fold in chronic allograft rejection with a close correlation between CCL5 and YB-1 mRNA expression in both conditions. Among three possible YB-1 binding sites in the CCL5 promoter, a critical element was mapped at -28/-10 bps. This site allowed up-regulation of CCL5 transcription in monocytic THP-1 and HUT78 T-cells and in human primary monocytes; however, it repressed transcription in differentiated macrophages. Conversely, YB-1 knockdown led to decreased CCL5 transcription and secretion in monocytic cells. We show that YB-1 is a cell-type specific regulator of CCL5 expression in infiltrating T-cells and monocytes/macrophages and acts as an adaptive controller of inflammation during kidney allograft rejection.
Raffetseder
Ute
U
Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany.
Rauen
Thomas
T
Djudjaj
Sonja
S
Kretzler
Matthias
M
En-Nia
Abdelaziz
A
Tacke
Frank
F
Zimmermann
Henning W
HW
Nelson
Peter J
PJ
Frye
Björn C
BC
Floege
Jürgen
J
Stefanidis
Ioannis
I
Weber
Christian
C
Mertens
Peter R
PR
D001706:Biopsy; D002465:Cell Movement; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D007249:Inflammation; D007668:Kidney / Q000473:pathology*; D016030:Kidney Transplantation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes; D051840:Y-Box-Binding Protein 1 / Q000276:immunology / Q000502:physiology*
D018946:Chemokine CCL5; D051840:Y-Box-Binding Protein 1