Deltex-1 is indispensible for the IL-6 and TGF-ß treatment-triggered differentiation of Th17 cells.

CSL(CBF1, Su(H) and LAG-1)-dependent Hes-1 signaling plays an important part in regulating Th17 cell differentiation. However, little is known about influence of CSL-independent Deltex-1 signaling on this subset. The current focus is on roles of the Deltex-1 signaling in the Th17 cell differentiation. IL-17-producing CD4+ T cell subpopulation could be induced in vitro by treatment of both IL-6 and TGF-ß. This could be reversed by knockdown of the deltex-1 gene, following the attenuation of retinoic acid-related orphan receptor γt (RORγt) and its DNA-binding activity in nuclei. Subsequently, Th17-associated cytokines generated by the treated cells were also diminished by the inhibition of Deltex-1 signaling, but the production of IL-10 was enhanced. Contrary to the alteration of RORγt, both zinc-finger transcription factor-3 (GATA3) and transcription factor Forkhead box P3 (Foxp3) were augmented at their mRNA and protein levels as well as DNA-binding activities with the emerging phenotypes of the corresponding cellular subpopulation and T-bet (encoded by TBX21) was not changed. These results reveal for the first time that Deltex-1 is indispensible for the IL-6 and TGF-ß treatment-triggered differentiation of Th17 cells, indicating that CSL-independent Deltex-1 signaling favors naïve CD4+ T cells to deviate into Th17 cells via the enhancement of RORγt/IL-17A.

Deltex1 suppresses T cell function and is a biomarker for diagnosis and disease activity of systemic lupus erythematosus.

OBJECTIVE: Deletion of Deltex1 (DTX1) in mice caused hyperactivation of T cells and lupus-like autoimmune syndromes, however, the association of DTX1 with human autoimmune diseases is totally unknown. This study investigated the role of DTX1 in human T cell functions and its correlation with disease activity in patients with SLE. METHODS: The influence of DTX1 on T cell function was evaluated using human primary cells. DTX1 expression in peripheral blood mononuclear cells (PBMCs) from healthy controls and SLE patients was measured by quantitative real-time PCR and the SLEDAI was used to assess disease activity. RESULTS: After stimulation with anti-CD3 and anti-CD28, silencing of DTX1 expression enhanced IFN-γ secretion by human T cells. The expression of DTX1 in PBMCs was significantly lower in 100 SLE patients than in 50 age- and sex-matched healthy controls (DTX1/glyceraldehyde 3-phosphate dehydrogenase, 0.452 vs 1.269, P < 0.001). The area under the receiver operator characteristics curve of the model was 0.737 (95% CI 0.658, 0.815). Intriguingly, a low DTX1 level in T cells led to high IFN-γ production in SLE patients and had a correlation with severe disease activity. In addition, low DTX1 expression in SLE patients was associated with active LN, lung involvement or hypocomplementaemia. CONCLUSION: Knockdown DTX1 expression in human T cells reduced IFN-γ secretion. DTX1 expression in the PBMCs was significantly lower in SLE patients and had an inverse correlation with disease activity, indicating that the DTX1 level may be a good disease marker of SLE.

The associations between Deltex1 and clinical characteristics of breast cancer.

BACKGROUND: Deltex 1 (DTX1) is a single transmembrane protein with ubiquitin E3 ligase activity which has been found to play a role in the development of several cancers. We aimed to investigate the associations between DTX1 and breast cancer (BC). METHODS: We explored the roles and mechanisms of DTX1 in BC by using BC cell lines in vitro. Levels of DTX1 in serum and tissues were determined in 316 patients with BC, 102 patients with fibroadenoma, and 113 healthy controls by immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR). The associations between DTX1 and clinical characteristics of BC were analyzed using multivariate analysis and Cox regression survival analysis. RESULTS: Lower levels of DTX1 promoted BC cell proliferation, migration, and invasion. The cell growth and survival of BC might be regulated by DTX1 via the Notch signaling pathway. Levels of DTX1 in BC tissues were lower compared to fibroadenoma tissues and peri-neoplastic breast tissues (P<0.01). A lower level of DTX1 was shown to be associated with advanced tumor grade (P=0.017), advanced clinical stage (P=0.031), positive lymph node metastasis (LNM) (P=0.009), and high Ki-67 index (P=0.023). Lower DTX1 expression was recognized as an impact factor for metastasis-free survival (MFS) in BC. CONCLUSIONS: Lower levels of DTX1 could promote BC cell proliferation and migration, and are associated with advanced BC. There is potential for DTX1 as a marker to assist the selection of new BC treatment.