Regulation of mRNA stability contributes to the function of innate lymphoid cells in various diseases.

Innate lymphoid cells (ILCs) are important subsets of innate immune cells that regulate mucosal immunity. ILCs include natural killer cells, innate lymphoid cells-1 (ILC1s), ILC2s, and ILC3s, which have extremely important roles in the immune system. In this review, we summarize the regulation of mRNA stability mediated through various factors in ILCs (e.g., cytokines, RNA-binding proteins, non-coding RNAs) and their roles in mediating functions in different ILC subsets. In addition, we discuss potential therapeutic targets for diseases such as chronic obstructive pulmonary disease, cancer, and pulmonary fibrosis by regulation of mRNA stability in ILCs, which may provide novel directions for future clinical research.

Hepatocyte growth factor-mediated apoptosis mechanisms of cytotoxic CD8+ T cells in normal and cirrhotic livers.

Intrahepatic stem/progenitor cells and cytotoxic CD8+ T cells (CD8+ T cells) in the cirrhotic liver undergo apoptosis, which potentially facilitates progression to cancer. Here, we report that hepatocyte growth factor (HGF) signaling plays an important role in promoting normal and damaged liver CD8+ T cell Fas-mediated apoptosis through its only receptor, c-Met. In addition to binding with HGF, c-Met also binds to Fas to form a complex. Using a diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis mouse model, immunostaining, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, we found that HGF secretion was significantly higher at 10 weeks post-DEN, the liver cirrhotic phase (LCP), than at 3 weeks post-DEN, the liver fibrotic phase (LFP). Correspondingly, differences in CD8+ T cell proliferation and apoptosis were noted between the two phases. Interestingly, staining and TUNEL assays revealed lower smooth muscle actin (α-SMA)+ cell apoptosis, a marker for hepatic stellate cells (HSCs), in the LFP group than in the LCP group, which suggested a beneficial correlation among HGF, CD8+ T cells and HSCs in improving the fibrotic load during damaged liver repair. In cultures, when met different concentrations of recombinant HGF (rHGF), phytohemagglutinin (PHA)-stimulated naive mouse splenic CD8+ T cells (pn-msCD8+ T cells) responded differently; as increases in rHGF increased were associated with decreases in the clonal numbers of pn-msCD8+ T cells, and when the rHGF dose was greater than 200 ng/mL, the clonal numbers significantly decreased. In the presence of 400 ng/mL rHGF, the death-inducing signaling complex (DISC) can be directly activated in both nsCD8+ T cells and healthy human peripheral blood CD8+ T cells (hp-CD8+ T cells), as indicated by recruitment of FADD and caspase-8 because DISC forms via the recruitment of FADD and caspase-8, among others. These findings suggest that Fas-mediated apoptosis, may also indicate a regulatory role of HGF signaling in hepatic homeostasis.

TTP-mediated regulation of mRNA stability in immune cells contributes to adaptive immunity, immune tolerance and clinical applications.

Dendritic cells (DCs) form a sentinel network to induce protective immunity against pathogens or self-tolerance. mRNA stability is an important part of the post-transcriptional regulation (PTR) that controls the maturation and function of DCs. In this review, we summarize the effects of TTP-mediated regulation of mRNA stability in DCs, focusing on DC maturation and antigen presentation, T cell activation and differentiation, immune tolerance and inflammation. We also discuss the potential DC-based immune treatment for HIV+ patients through regulation of mRNA stability. This review proposes the regulation of mRNA stability as a novel immune therapy for various inflammatory diseases, such as arthritis and dermatitis.

Inhibition of peroxisomal ß-oxidation by thioridazine increases the amount of VLCFAs and Aß generation in the rat brain.

Alzheimer's disease (AD) is characterized by the accumulation of the ß-amyloid peptide (Aß), which is generated from sequential cleavages of the amyloid precursor protein (APP) by ß-secretase (BACE1) and γ-secretase. Fatty acid alterations in AD brains have recently received substantial attention. Because increased very long chain fatty acid (VLCFA) levels in AD brains imply that peroxisomal ß-oxidation dysfunction may be associated with AD pathogenesis, we investigated the effects of impaired peroxisomal ß-oxidation on Aß generation in vivo and in vitro using thioridazine, a selective peroxisomal ß-oxidation inhibitor. Under the experimental conditions, thioridazine caused VLCFA accumulation and increases in Aß(40) content, APP immunoreactivity and APP(751+770) mRNA expressions in the rat cerebral cortex. A correlation analysis showed that the Aß(40) levels were positively correlated with the cortex C(24:0) and C(26:0) levels. Additionally, the primary cerebral cortex neurons treated with this compound showed increases in APP(751+770) mRNA, APP protein, BACE1 mRNA and protein, and secreted Aß40 levels. This work supports an emerging viewpoint that impaired peroxisomal function may play an important role in the progression of AD pathology.