Regulatory T cells negatively regulate neovasculature of airway remodeling via DLL4-Notch signaling.

Regulatory T cells (Treg) have been shown to prevent the development of allergic asthma; however, the role of Treg in asthma with established airway remodeling is unknown. To address this, we exploited an OVA-induced chronic asthma mouse model wherein Treg were adoptively transferred to the mice at chronic stage of the model. We found that among the structural alterations of airway remodeling, Treg selectively reduced the vessel numbers in both peritracheal and peribronchial regions and the lung parenchyma. Extracellular matrix deposition, mucus metaplasia, muscular hyperplasia, and vasodilation, as were also induced by chronic allergen challenge, were not affected by Treg. TUNEL staining of the lung sections revealed an increased endothelial cell (EC) apoptosis in mice receiving Treg transfers compared with their asthmatic counterparts. By using Matrigel angiogenesis assays, we showed that Treg inhibited EC angiogenesis both in vitro and in vivo. Treg preferentially expressed Notch ligand DLL4, and an anti-DLL4 blocking Ab abrogated the inhibitory effect of Treg on EC tube formation. In vivo, decreased airway and lung vessel numbers as well as ameliorated airway hyperresponsiveness after Treg transfers were reverted when Treg-derived DLL4 signal was blocked by the anti-DLL4 Ab. Our findings demonstrate a novel function of Treg whereby Treg down-regulate remodeling angiogenesis via proapoptotic DLL4-Notch signaling, and suggest a therapeutic potential of Treg in alleviating airway hyperresponsiveness of chronic asthma.

Ribavirin enhances interferon signaling via stimulation of mTOR and p53 activities.

Cellular mechanisms involving the enhancement of interferon (IFN) signaling by ribavirin remain poorly understood. Here, we identified a novel role of ribavirin in the communication between p53 and the mammalian target of rapamycin (mTOR) signaling. Ribavirin activates p53 by stimulating mTOR and promoting the interaction between mTOR and p53. Activated p53 stimulates the transcription of IFN regulatory factor 9 and subsequently enhances IFN signaling. Furthermore, ribavirin-induced activation of mTOR and p53 enhances IFN-dependent signaling for the IFN-alpha/ribavirin combined treatment. We conclude that ribavirin enhances activities of mTOR and p53, which may account for its antiviral and antitumor effects.

In-vitro effects of dexamethasone on cellular proliferation, apoptosis, and Na+-K+-ATPase activity of bovine corneal endothelial cells.

PURPOSE: To assess the in-vitro effects of dexamethasone (DEX) on the proliferation, apoptosis, and Na+-K+-ATPase activity of bovine corneal endothelial cells. METHODS: Bovine corneal endothelial cells were cultured with DEX ranging from 10-10 to 10-3 M. The effect of DEX on the proliferation was analyzed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay. Apoptosis and necrosis were detected by staining with fluorescein-conjugated annexin V and propidium iodide, followed by flow cytometry. The effect of DEX on Na+-K+-ATPase activity was evaluated using non-isotopic methods. RESULTS: DEX did not affect cellular proliferation or induce apoptosis/necrosis from 10-10 to 10-5 M. At 10-4 and 10-3 M, DEX significantly decreased proliferation and increased apoptosis and/or necrosis. DEX significantly increased the Na+-K+-ATPase activity from 10-8 to 10-6 M, with the maximal effect at 10-6 M (p < 0.01); this effect was inhibited by RU38486, an antiglucocorticoid molecule. CONCLUSIONS: Bovine corneal endothelial cells express glucocorticoid receptor (GR) mRNA and protein. DEX decreases cell proliferation and induces cellular apoptosis and/or necrosis at high concentrations. DEX also increases the Na+-K+-ATPase activity at certain concentrations.