The plasticity of T lymphocytes induced by epigenetic modifications of gene promoters may play a pivotal role in controlling their effector functions, which are sometimes causally associated with immune disorders. IL -17-producing T cells, which induce type 17 immune responses, are newly identified pathogenic effector cells. The type 1 signature cytokine IFN-γ strongly inhibits their differentiation, indicating a mutually exclusive relationship between type 17- and type 1-immune responses. However, many reports indicate the presence of a unique IL-17/IFN-γ-double producing T-cell subset in various inflammatory settings, although the mechanisms responsible for their development and their precise functions remain unclear. Here, we demonstrate that IL-12 permits the conversion of mouse IL-17-producing CD8(+) T (Tc17) cells to IL-17/IFN-γ-double producing CD8(+) T (Tc17/IFN-γ) cells, and that this conversion is due to repressive epigenetic modifications of Socs3 gene promoters. Moreover, we show that SOCS3 strongly regulates the capability of Tc17 cells to produce IL-17, in addition to regulating the expression of the type 17-master regulator RORγt. These findings elucidate the mechanisms underlying the conversion of Tc17 cells into Tc17/IFN-γ cells. As these cells are known to have potent antitumor activities, manipulation of these conversion mechanisms for therapeutic tumor immunity may be possible.
The improved thermal dolorimeter developed by Fukumoto has made it easy to measure thermal pain thresholds, but mechanical stimulations may be included as the probe is pressed into the skin. In order to evaluate these effects of mechanical stimulation on the improved thermal dolorimeter, the pain threshold temperatures were measured by a probe pressed to the human skin surface with weighting loads from 0.5 to 2.5 kgf. The loads of 2.0-2.5 kgf felt invasive to 8 of the 12 subjects, i.e., they experienced pain and numbness. The threshold temperature of one of these subjects, who developed water blisters around load-added area on the skin after the experiments, exceeded 50°C. The result that no significant difference could be found among the thresholds at the loads of over 2.0 kgf suggests the load of less than 2.0 kgf should be kept to execute proper experiments. In order to investigate other effects on thermal property by compressing, the blood flow was measured when the skin was compressed and three dimensional heat transfer simulations were conducted. The results of the simulations demonstrated that the temperatures of the heat source which were measurable in practice differed approximately 1 to 2°C from the true thresholds. The velocity of heating is also increased and subjects will be given stronger feelings of heating.
Scalp potentials evoked by electrical stimulation of the tooth pulp can be diminished in amplitude by electroacupuncture. This diminution goes generally in inverse with the increase in subjective pain threshold.
Introduction: Despite the widespread use of general anaesthetics, the mechanisms mediating their effects are still not understood. Although suppressed in most parts of the brain, neuronal activity, as measured by FOS activation, is increased in the hypothalamic supraoptic nucleus (SON) by numerous general anaesthetics, and evidence points to this brain region being involved in the induction of general anaesthesia and natural sleep. Posttranslational modifications of proteins, including changes in phosphorylation, enable fast modulation of protein function which could be underlying the rapid effects of general anaesthesia. In order to identify potential phosphorylation events in the brain mediating general anaesthesia effects, we have explored the phosphoproteome responses in the rat SON, and compared these to cingulate cortex (CC) which displays no FOS activation is response to general anaesthetics. Methods: Adult Sprague-Dawley rats were treated with isoflurane for 15 minutes. Proteins from the CC and SON were extracted and processed for Nano-LC Mass Spectrometry (LC-MS/MS). Phosphoproteomic determinations were performed by LC-MS/MS. Results: We found many changes in the phosphoproteomes of both the CC and SON in response to 15 minutes of isoflurane exposure. Pathway analysis indicated that proteins undergoing phosphorylation adaptations are involved in cytoskeleton remodelling and synaptic signalling events. Importantly, changes in protein phosphorylation appeared to be brain region-specific suggesting that differential phosphorylation adaptations might underlie the different neuronal activity responses to general anaesthesia between the CC and SON. Conclusion: In summary, these data suggest that rapid posttranslational modifications in proteins involved in cytoskeleton remodelling and synaptic signalling events might mediate the central mechanisms mediating general anaesthesia.
