In:
Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 96, No. 5 ( 2014-06-19), p. 675-684
Abstract:
Whereas GCs have been demonstrated to be beneficial for transplantation patients, the pharmacological mechanisms remain unknown. Herein, the role of GR signaling was investigated via a pharmacological approach in a murine allogeneic skin transplantation model. The GC Dex, a representative GC, significantly relieved allograft rejection. In Dex-treated allograft recipient mice, CD11b+Gr1+ MDSCs prolonged graft survival and acted as functional suppressive immune modulators that resulted in fewer IFN-γ-producing Th1 cells and a greater number of IL-4-producing Th2 cells. In agreement, Dex-treated MDSCs promoted reciprocal differentiation between Th1 and Th2 in vivo. Importantly, the GR is required in the Dex-induced MDSC effects. The blocking of GR with RU486 significantly diminished the expression of CXCR2 and the recruitment of CD11b+Gr1+ MDSCs, thereby recovering the increased MDSC-suppressive activity induced by Dex. Mechanistically, Dex treatment induced MDSC iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated the MDSC-suppressive function and the effects on T cell differentiation. This study shows MDSCs to be an essential component in the prolongation of allograft survival following Dex or RU486 treatment, validating the GC–GR–NO signaling axis as a potential therapeutic target in transplantation.
Type of Medium:
Online Resource
ISSN:
0741-5400
,
1938-3673
DOI:
10.1189/jlb.2HI1113-611RR
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2014
detail.hit.zdb_id:
2026833-6
SSG:
12