Proenkephalin+ regulatory T cells expanded by ultraviolet B exposure maintain skin homeostasis with a healing function.

Regulatory T (Treg) cells, expressing CD25 (interleukin-2 receptor α chain) and Foxp3 transcription factor, maintain immunological self-tolerance and suppress various immune responses. Here we report a feature of skin Treg cells expanded by ultraviolet B (UVB) exposure. We found that skin Treg cells possessing a healing function are expanded by UVB exposure with the expression of an endogenous opioid precursor, proenkephalin (PENK). Upon UVB exposure, skin Treg cells were expanded with a unique TCR repertoire. Also, they highly expressed a distinctive set of genes enriched in "wound healing involved in inflammatory responses" and the "neuropeptide signaling pathway," as indicated by the high expression of Penk. We found that not only was PENK expression at the protein level detected in the UVB-expanded skin Treg (UVB-skin Treg) cells, but that a PENK-derived neuropeptide, methionine enkephalin (Met-ENK), from Treg cells promoted the outgrowth of epidermal keratinocytes in an ex vivo skin explant assay. Notably, UVB-skin Treg cells also promoted wound healing in an in vivo wound closure assay. In addition, UVB-skin Treg cells produced amphiregulin (AREG), which plays a key role in Treg-mediated tissue repair. Identification of a unique function of PENK+ UVB-skin Treg cells provides a mechanism for maintaining skin homeostasis.

How UV Light Touches the Brain and Endocrine System Through Skin, and Why.

The skin, a self-regulating protective barrier organ, is empowered with sensory and computing capabilities to counteract the environmental stressors to maintain and restore disrupted cutaneous homeostasis. These complex functions are coordinated by a cutaneous neuro-endocrine system that also communicates in a bidirectional fashion with the central nervous, endocrine, and immune systems, all acting in concert to control body homeostasis. Although UV energy has played an important role in the origin and evolution of life, UV absorption by the skin not only triggers mechanisms that defend skin integrity and regulate global homeostasis but also induces skin pathology (e.g., cancer, aging, autoimmune responses). These effects are secondary to the transduction of UV electromagnetic energy into chemical, hormonal, and neural signals, defined by the nature of the chromophores and tissue compartments receiving specific UV wavelength. UV radiation can upregulate local neuroendocrine axes, with UVB being markedly more efficient than UVA. The locally induced cytokines, corticotropin-releasing hormone, urocortins, proopiomelanocortin-peptides, enkephalins, or others can be released into circulation to exert systemic effects, including activation of the central hypothalamic-pituitary-adrenal axis, opioidogenic effects, and immunosuppression, independent of vitamin D synthesis. Similar effects are seen after exposure of the eyes and skin to UV, through which UVB activates hypothalamic paraventricular and arcuate nuclei and exerts very rapid stimulatory effects on the brain. Thus, UV touches the brain and central neuroendocrine system to reset body homeostasis. This invites multiple therapeutic applications of UV radiation, for example, in the management of autoimmune and mood disorders, addiction, and obesity.

Turning on stem cell cardiogenesis with extremely low frequency magnetic fields.

Modulation of stem cell differentiation is an important assignment for cellular engineering. Embryonic stem (ES) cells can differentiate into cardiomyocytes, but the efficiency is typically low. Here, we show that exposure of mouse ES cells to extremely low frequency magnetic fields triggered the expression of GATA-4 and Nkx-2.5, acting as cardiac lineage-promoting genes in different animal species, including humans. Magnetic fields also enhanced prodynorphin gene expression, and the synthesis and secretion of dynorphin B, an endorphin playing a major role in cardiogenesis. These effects occurred at the transcriptional level and ultimately ensued into a remarkable increase in the yield of ES-derived cardiomyocytes. These results demonstrate the potential use of magnetic fields for modifying the gene program of cardiac differentiation in ES cells without the aid of gene transfer technologies and may pave the way for novel approaches in tissue engineering and cell therapy.

Pulsed magnetic field induced "analgesia" in the land snail, Cepaea nemoralis, and the effects of mu, delta, and kappa opioid receptor agonists/antagonists.

A brief exposure to a pulsed magnetic field (Cnp: patent pending) had significant antinociceptive or "analgesic" effects in the land snail, Cepaea nemoralis, as evidenced by an increase in the latency of response to a warmed (40 degrees C) surface. This analgesia was in part opioid mediated being significantly reduced, but not eliminated: by the prototypic opiate antagonist, naloxone; the mu (mu) opioid receptor directed antagonists, naloxazine or beta-funaltrexamine, and the delta (delta) opioid receptor directed antagonists, naltrindole-5'-isothiocyanate or ICI 174,864. However the Cnp induced analgesia was unaffected by the kappa (kappa) opioid receptor directed antagonist, nor-binaltorphimine. The delta 1 and delta 2 opioid receptor directed agonists, (DPDPE, [D-Pen2,D-Pen5]enkephalin), (deltorphin, [D-Ala2,Glu4]), respectively, also had significant differential analgesic effects, supporting a functional delta opioid receptor mediated enkephalinergic mechanism in Cepaea. These results suggest that this specific pulsed magnetic field (Cnp) elicits significant analgesic effects through mechanisms that, in part, involve delta and, to a lesser extent mu opioid receptors.

A comparison between microwave irradiation and decapitation: basal levels of dynorphin and enkephalin and the effect of chronic morphine treatment on dynorphin peptides.

Opioid peptides were analysed in tissue extracts of various brain structures and the pituitary gland from rats sacrificed by microwave irradiation, and compared with peptide levels in tissue extracts from decapitated rats. Dynorphin A, dynorphin B and Leu-enkephalinArg6, derived from prodynorphin, and Met-enkephalinArg6Phe7 from proenkephalin, were measured. Basal immunoreactive levels of dynorphin A and B were consistently higher in extracts from microwave-irradiated rats, whereas in these extracts immunoreactive levels of Leu-enkephalinArg6, an endogenous metabolite of dynorphin peptides, were either lower than, the same as or higher than in decapitated rats. Immunoreactive levels of Met-enkephalinArg6Phe7 were higher in microwave-irradiated rats. Effects of morphine treatment on prodynorphin peptide levels were evaluated and compared with previous findings in decapitated rats. Dynorphin immunoreactive levels were higher in the nucleus accumbens and striatum of morphine-tolerant rats than in corresponding areas in saline-treated rats. These results indicate tissue-specific metabolism of prodynorphin peptides and show that metabolism of opioid peptides occurs during the dissection procedure after decapitation of the rat even though precautions are taken to minimize degradation.

Radiation hormesis. A new concept in radiological science.

Low-dose ionizing radiation caused definite stimulation of immune reactions both in humans and mice. The PFC reaction in response to SRBC immunization and the NK activity of the splenocytes were significantly enhanced after low-dose whole body irradiation. Activation of the T lymphocytes, especially the TH, with increased production of IL-2, might be a critical step in the whole process of immunoenhancement. A single dose of 75 mGy X-rays caused significant lowering of hypothalamic M-Enk content as well as serum corticosterone level. The increased serum testosterone level would exert an inhibitory influence on the CRF-ACTH-CS system to keep the blood corticosterone at a lower than normal level which might facilitate the immune reactions in the SRBC-immunized animals. The increased catecholamines in the spleen would probably reinforce this effect resulting in immunoenhancement. Low-dose ionizing radiation caused increased repair of the genetic material at both the molecular and subcellular levels. The UDS of human and murine lymphocytes was augmented by single or continuous low-dose irradiation. The stimulation of DNA polymerase activity might be responsible for such effects. Exposure to very small doses of low LET radiation could induce in different tissues an adaptive response which alleviated chromosome damage caused by subsequent larger dose radiation. Such an adaptive response could be induced both in vivo and in vitro in different animal species. The induced adaptive response faded away after 3 cell cycles could be re-induced by a second exposure to low-dose radiation. The mechanism of the inductive process needs further study.(ABSTRACT TRUNCATED AT 250 WORDS)