The role of the dorsal noradrenergic pathway of the brain (locus coeruleus) in the regulation of liver cytochrome P450 activity

Our previous study conducted after intracerebroventricular DSP-4 injection showed an important stimulating role of a brain noradrenergic system in the neuroendocrine regulation of liver cytochrome P450 (CYP) expression. The aim of the present research was to study involvement of the dorsal noradrenergic pathway of the brain (originating from the locus coeruleus) in the expression of liver cytochrome P450. The experiment was carried out on male Wistar rats. Local injection of 6-hydroxydopamine to the locus coeruleus selectively decreased noradrenaline level in the brain (e.g. in the hypothalamus). The serum concentration of the growth hormone rose, while that of the thyroid hormones or corticosterone remained unchanged. A comparative study into cytochrome P450 isoform activity revealed significant increases in the activity of liver CYP2C11 and CYP3A after administration of 6-hydroxydopamine. The observed increase in the activity of CYP2C11 positively correlated with that in CYP protein level, while the enhanced activity of CYP3A was not accompanied with a simultaneous change in the enzyme protein. A 5-day-injection of noradrenaline into the lateral ventricles produced opposite effects on the CYP isoforms. It is concluded that damage to or activation of the dorsal noradrenergic innervation of the periventricular nucleus of the hypothalamus containing somatostatin (a growth hormone release-inhibiting factor) may be responsible for the changes observed in the activity of isoforms CYP2C11 and CYP3A that are regulated by the growth hormone. The obtained results indicate that the dorsal noradrenergic pathway plays an inhibitory (but not a crucial) role in the neuroendocrine regulation of cytochrome P450

Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity

BACKGROUND: T cell tolerance of allergic cutaneous contact sensitivity (CS) induced in mice by high doses of reactive hapten is mediated by suppressor cells that release antigen-specific suppressive nanovesicles. OBJECTIVE: To determine the mechanism(s) of immune suppression mediated by the nanovesicles. METHODS: T cell tolerance was induced by i.v. injections of hapten conjugated to self antigens of syngeneic erythrocytes and subsequent contact immunization with the same hapten. Lymph node and spleen cells from tolerized or control donors were harvested and cultured to produce a supernatant containing suppressive nanovesicles that were isolated for testing in active and adoptive cell transfer models of CS. RESULTS: Tolerance was shown due to exosome-like nanovesicles in the supernatant of CD8(+) suppressor T cells that were not Treg. Antigen specificity of the suppressive nanovesicles was conferred by a surface coat of antibody light chains, or possibly whole antibody, allowing targeted delivery of selected inhibitory miRNA-150 to CS effector T cells. Nanovesicles also inhibited CS in actively sensitized mice after systemic injection at the peak of the responses. The role of antibody and miRNA-150 was established by tolerizing either panimmunoglobulin deficient JH(-/-) or miRNA-150(-/-) mice that produced non-suppressive nanovesicles. These nanovesicles could be made suppressive by adding antigen-specific antibody light chains or miRNA-150, respectively. CONCLUSIONS: This is the first example of T cell regulation via systemic transit of exosome-like nanovesicles delivering a chosen inhibitory miRNA to target effector T cells in an antigen-specific manner by a surface coating of antibody light chains