SummarySystemic lupus erythematosus (SLE) is a systemic autoimmune disease with abnormal T cell immune responses. We hypothesized that aberrant expression of microRNAs (miRNAs) in T cells may contribute to the pathogenesis of SLE. First, we analysed the expression profiles of 270 human miRNAs in T cells from five SLE patients and five healthy controls and then validated those potentially aberrant-expressed miRNAs using real-time polymerase chain reaction (PCR). Then, the expression of mRNAs regulated by these aberrantexpressed miRNAs was detected using real-time PCR. Finally, miRNA transfection into Jurkat T cells was conducted for confirming further the biological functions of these miRNAs. The initial analysis indicated that seven miRNAs, including miR-145, miR-224, miR-513-5p, miR-150, miR516a-5p, miR-483-5p and miR-629, were found to be potentially abnormally expressed in SLE T cells. After validation, under-expressed miR-145 and over-expressed miR-224 were noted. We further found that STAT1 mRNA targeted by miR-145 was over-expressed and apoptosis inhibitory protein 5 (API5) mRNA targeted by miR-224 was under-expressed in SLE T cells. Transfection of Jurkat cells with miR-145 suppressed STAT1 and miR-224 transfection suppressed API5 protein expression. Over-expression of miR-224 facilitates activation-induced cell death in Jurkat cells. In the clinical setting, the increased transcript levels of STAT1 were associated significantly with lupus nephritis. In conclusion, we first demonstrated that miR-145 and miR-224 were expressed aberrantly in SLE T cells that modulated the protein expression of their target genes, STAT1 and API5, respectively. These miRNA aberrations accelerated T cell activation-induced cell death by suppressing API5 expression and associated with lupus nephritis by enhancing signal transducer and activator of transcription-1 (STAT)-1 expression in patients with SLE.

Crosstalk between transforming growth factor beta (TGF-β) signaling and p53 has a critical role in cancer progression. TGF-β signals via Smad and non-Smad pathways. Under normal conditions, wild-type p53 forms a complex with Smad2/3 and co-activates transcription of a variety of tumor suppressor genes, resulting in tumor suppressive effects. Thus, p53 stability is essential in progression of tumor suppressive responses mediated by TGF-β signaling. However, it remains unknown whether p53 stability is regulated by TGF-β. In the current study, we identify that USP15 binds to and stabilizes p53 through deubiquitination in U2OS and HEK293 cells. TGF-β promotes the translation of USP15 through activation of mammalian target of rapamycin by the phosphoinositide 3-kinase/AKT pathway. Upregulation of USP15 translation links the crosstalk between TGF-β signaling and p53 stability, allowing this cytokine to have a critical role in cancer progression.

We investigated whether premature telomeric loss occurred in peripheral polymorphonuclear neutrophils (PMN) as well as mononuclear cells (MNC) from patients with systemic lupus erythematosus (SLE). We measured the telomere length of MNC and PMN in 60 SLE patients and 26 sex-, race- and age-matched healthy volunteers by Southern blotting with chemiluminescence method. The possible predisposing factors associated with telomere change were also analysed. We found the telomere length of MNC and PMN shortened with age in different degrees in both SLE and control groups. Compared to the control group, the telomere length was shortened in both SLE-MNC (6.08 kb in SLE versus 6.71 kb in control, P = 0.0008) and PMN (6.24 kb in SLE versus 6.75 kb in control, P = 0.0025). The average reduction in telomere length in SLE patients was equivalent to a premature senescence of 16.5 years in MNC and 13.4 years in PMN. In addition, the accelerated telomere shortening was more prominent in SLE patients younger than 45 years old. SLE disease activity (SLEDAI) contributed remarkably to the accelerated telomere erosion, at least in PMN. Moreover, the telomere length of MNC was significantly shorter than PMN in the same SLE patients with leukopenia and lymphopenia. These data suggested that MNC and PMN from patients with SLE displayed premature and accelerated telomere shortening that SLE is an independent factor for it.

Objective To investigate whether the aberrant expression of non-coding RNAs (ncRNAs) in T cells from patients with systemic lupus erythematosus (SLE) could contribute to the pathogenesis of lupus. Methods Expression profiles of RNA transcripts in T cells from three patients with SLE and three controls were analyzed by microarray analysis. Potentially aberrant-expressed ncRNAs were validated using T cell samples from 23 patients with SLE and 17 controls. Transfection studies and microarray analyses were conducted to search for any gene expression that is regulated by specific ncRNAs. Results Initial analysis revealed differential expression of 18 ncRNAs in SLE T cells. After validation, decreased expression of H/ACA box small nucleolar RNA 12 (SNORA12) was confirmed in SLE T cells (0.69-fold, P = 0.007) compared with normal T cells, and its expression level was inversely associated with higher SLE disease activity scores. Jurkat cells transfected with a plasmid encoding SNORA12 showed increased expression of two genes and decreased expression of 15 genes in Jurkat cells. These changes of gene expression were significantly associated with the SLE pathway in the Kyoto Encyclopedia of Genes and Genomes map using microarray analysis. Overexpression of SNORA12 altered the expression of CD69, decreased the expression of histone cluster 1 H4 family member k (HIST1H4K), inhibited the secretion of interferon gamma and the expression of HIST1H4K was increased in SLE T cells. Conclusion Among the ncRNAs, we found that the expression level of SNORA12, which belongs to the family of small nucleolar RNAs, was lower in SLE T cells and affected T cell function. This novel finding suggests that aberrant-expressed snoRNAs lead to dysfunction of T cells and may be involved in the immunopathogenesis of SLE.