MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GVHD

被引：93

作者：

Stickel, Natalie ^{[1
,2
,3
]}

Prinz, Gabriele ^{[1
]}

Pfeifer, Dietmar ^{[1
]}

Hasselblatt, Peter ^{[4
]}

Schmitt-Graeff, Annette ^{[5
]}

Follo, Marie ^{[1
]}

Thimme, Robert ^{[4
]}

Finke, Juergen ^{[1
]}

Duyster, Justus ^{[1
]}

Salzer, Ulrich ^{[6
,7
,8
]}

Zeiser, Robert ^{[1
,9
]}

机构：

[1] Univ Freiburg, Med Ctr, Dept Hematol Oncol & Stem Cell Transplantat, D-79106 Freiburg, Germany

[2] Univ Freiburg, Spemann Grad Sch Biol & Med, D-79106 Freiburg, Germany

[3] Univ Freiburg, Fac Biol, D-79106 Freiburg, Germany

[4] Univ Freiburg, Med Ctr, Clin Gastroenterol Hepatol Endocrinol & Infect Di, Dept Med, D-79106 Freiburg, Germany

[5] Univ Freiburg, Med Ctr, Dept Pathol, D-79106 Freiburg, Germany

[6] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany

[7] Univ Med Ctr Freiburg, Dept Rheumatol & Clin Immunol, Freiburg, Germany

[8] Univ Freiburg, D-79106 Freiburg, Germany

[9] Univ Freiburg, Ctr Biol Signaling Studies, D-79106 Freiburg, Germany

来源：

BLOOD | 2014年 / 124卷 / 16期

关键词：

VERSUS-HOST-DISEASE; SYSTEMIC-LUPUS-ERYTHEMATOSUS; TNF-ALPHA; TUMOR ACTIVITY; MARROW; EXPRESSION; ASSOCIATION; INHIBITION; INDUCTION; BIOLOGY;

D O I：

10.1182/blood-2014-04-569046

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Acute graft-versus-host disease (GVHD) limits the success of allogeneic hematopoietic cell transplantation (allo-HCT); therefore, a better understanding of its biology may improve therapeutic options. We observed miR-146a up-regulation in T cells of mice developing acute GVHD compared with untreated mice. Transplanting miR-146a(-/-) T cells caused increased GVHD severity, elevated tumor necrosis factor (TNF) serum levels, and reduced survival. TNF receptor-associated factor 6 (TRAF6), a verified target of miR-146a, was up-regulated in miR-146a(-/-) T cells following alloantigen stimulation. Higher TRAF6 levels translated into increased nuclear factor-kappa B activity and TNF production in miR-146a(-/-) T cells. Conversely, the detrimental effect of miR-146a deficiency in T cells was antagonized by TNF blockade, whereas phytochemical induction of miR-146a or its overexpression using a miR-146a mimic reduced GVHD severity. In humans, the minor genotype of the single nucleotide polymorphism rs2910164 in HCT donors, which reduces expression of miR-146a, was associated with severe acute GVHD (grade III/IV). We show that miR-146a functions as a negative regulator of donor T cells in GVHD by targeting TRAF6, leading to reduced TNF transcription. Because miR-146a expression can be exogenously enhanced, our results provide a novel targeted molecular approach to mitigate GVHD.

引用

页码：2586 / 2595

页数：10