| RRC ID |
48755
|
| 著者 |
Richard EM, Thiyagarajan T, Bunni MA, Basher F, Roddy PO, Siskind LJ, Nietert PJ, Nowling TK.
|
| タイトル |
Reducing FLI1 levels in the MRL/lpr lupus mouse model impacts T cell function by modulating glycosphingolipid metabolism.
|
| ジャーナル |
PLoS One
|
| Abstract |
Systemic Lupus erythematosus (SLE) is an autoimmune disease caused, in part, by abnormalities in cells of the immune system including B and T cells. Genetically reducing globally the expression of the ETS transcription factor FLI1 by 50% in two lupus mouse models significantly improves disease measures and survival through an unknown mechanism. In this study we analyze the effects of reducing FLI1 in the MRL/lpr lupus prone model on T cell function. We demonstrate that adoptive transfer of MRL/lpr Fli1(+/+) or Fli1(+/-) T cells and B cells into Rag1-deficient mice results in significantly decreased serum immunoglobulin levels in animals receiving Fli1(+/-) lupus T cells compared to animals receiving Fli1(+/+) lupus T cells regardless of the genotype of co-transferred lupus B cells. Ex vivo analyses of MRL/lpr T cells demonstrated that Fli1(+/-) T cells produce significantly less IL-4 during early and late disease and exhibited significantly decreased TCR-specific activation during early disease compared to Fli1(+/+) T cells. Moreover, the Fli1(+/-) T cells expressed significantly less neuraminidase 1 (Neu1) message and decreased NEU activity during early disease and significantly decreased levels of glycosphingolipids during late disease compared to Fli1(+/+) T cells. FLI1 dose-dependently activated the Neu1 promoter in mouse and human T cell lines. Together, our results suggest reducing FLI1 in lupus decreases the pathogenicity of T cells by decreasing TCR-specific activation and IL-4 production in part through the modulation of glycosphingolipid metabolism. Reducing the expression of FLI1 or targeting the glycosphingolipid metabolic pathway in lupus may serve as a therapeutic approach to treating lupus.
|
| 巻・号 |
8(9)
|
| ページ |
e75175
|
| 公開日 |
2013-1-1
|
| DOI |
10.1371/journal.pone.0075175
|
| PII |
PONE-D-13-11673
|
| PMID |
24040398
|
| PMC |
PMC3769295
|
| MeSH |
Adoptive Transfer
Animals
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
Disease Models, Animal
Disease Progression
Female
Glycosphingolipids / metabolism*
Homeodomain Proteins / metabolism
Humans
Interleukin-4 / biosynthesis
Jurkat Cells
Lupus Erythematosus, Systemic / immunology*
Lupus Erythematosus, Systemic / metabolism*
Lymphocyte Activation
Mice
Mice, Inbred MRL lpr
Proto-Oncogene Protein c-fli-1 / deficiency
Proto-Oncogene Protein c-fli-1 / metabolism*
Receptors, Antigen, T-Cell / metabolism
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism*
|
| IF |
2.74
|
| 引用数 |
17
|
|
WOS 分野
|
IMMUNOLOGY
|
| リソース情報 |
| 遺伝子材料 |
B6N BAC Mouse (RDB07573) B6Ng01-067D09 |
