Expression of preprotachykinin-A and neuropeptide-Y messenger RNA in the thymus

The preprotachykinin-A gene, the common gene of mRNAs encoding both substance-P (SP) and neurokinin- A (NKA), was shown to be expressed in Sprague-Dawley rat thymus by detection of specific mRNA in gel-blot analyses. In situ hybridization revealed dispersed PPT-A-labeled cells in sections from rat thymus, with a concentration of grains over a subpopulation of cells in the thymic medulla. Also, neuropeptide-Y mRNA-expressing cells were found in the rat thymus, primarily in the thymic medulla. Rat thymic extracts contained SP-like immunoreactivity (SP-LI), and the major part of the immunoreactivity coeluted with authentic SP and SP sulfoxide standards. SP-LI was also detected in human thymus, which contained between 0.09-0.88 ng SP-LI/ g wet wt. Evidence for translation of preprotachykinin- A mRNA in the rat thymus was obtained from the demonstration of NKA-LI in thymic cells with an epithelial-like cell morphology. Combined with previous observations on the immunoregulatory roles of tachykinin peptides and the existence of specific receptors on immunocompetent cells, the demonstration of intrathymic synthesis of NKA suggests a role for NKA-LI peptides in T-cell differentiation in the thymus

Immunomodulatory properties of cyclic hexapeptide oxytocin antagonists

peer reviewedA pharmacological manipulation of cryptocrine cell-to-cell signaling was tested by the investigation of the immunomodulatory properties of novel cyclic hexapeptide oxytocin (OT) antagonists (MSD Research Laboratories). The compounds were found to significantly inhibit the productions of IL-1ß and IL-6 elicited by anti-CD3 treatment oh human whole blood cells cultures (WBC). Cytokine productions were more significantly reduced by OT antagonists in WBC derived from female volunteers than in those obtained from male donors, suggesting an influence of sex steroids on the expression of NHP receptors by immune cells. These observations support the concept of novel immunomodulating approaches through immune-specific neuropeptide antagonists, as well as the pharmacological value of such strategies in selective immunotherapy

Urinary excretion of immunoreactive luteinizing hormone-releasing hormone-like material and gonadotropins at different stages of life

LHRH-like immunoreactivity (IR LHRH) excreted in human urine spontaneously or after iv injection of LHRH was studied. It was characterized by gel filtration on carboxymethyl-cellulose and RIA using two antisera with different affinities for LHRH fragments. From these studies, it was suggested that the material excreted after iv injection of 1-10 LHRH was heterogeneous and contained at least 1-10 and 2-10 LHRH. In contrast the properties of endogenous urinary material were consistent with the absence of detectable intact decapeptide and the presence of 2-10 nonapeptide of LHRH as a major excretory product. In 24-h urines obtained from 292 normal subjects, IR LHRH, FSH, and LH were assayed and related to their chronological ages. The mean level of IR LHRH was found to be the lowest in male and female infants (3.2 and 2.9 ng/24 h), and to rise gradually in prepubertal boys and girls until 11 yr and markedly in postmenopausal women (49 ng/24 h). No significant differences of urinary IR LHRH excretion appeared between the last prepubertal aged subject and pubertal or adult subjects. A significant positive correlation between urinary IR LHRH and both FSH and LH was observed in prepubertal boys and girls, in pubertal boys, and (for LH only) in adult males. No correlation was observed in infants of either sex or in pubertal, adult, or postmenopausal females

Decreased Corticosensitivity in Quiescent Crohn's Disease: An Ex Vivo Study Using Whole Blood Cell Cultures

Corticosensitivity influences the degree and the duration of an inflammatory reaction by altering target cell responses to endogenous and/or exogenous glucocorticoids. Indeed, different clinical responses to glucocorticoids have been observed among patients with Crohn's disease, suggesting different degrees of corticosensitivity in these subjects. The purpose of this study was to compare the corticosensitivity of patients with quiescent Crohn's disease to that of healthy subjects (HS). Nineteen patients with quiescent Crohn's disease and 14 HS were studied; all patients were steroid-free for at least six months; 7 of the 19 were corticosteroid-dependent (CSD) and treated with nonglucocorticoid immunosuppressants at the time of the study. Corticosensitivity was measured by the inhibition of LPS-induced cytokine secretion in whole blood cell cultures treated with increasing concentrations (10(-9) to 10(-6) M) of dexamethasone. Tumor-necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) were measured using specific immunoassays. Crohn's disease patients had a markedly decreased dexamethasone-mediated inhibition of TNF-alpha (P < 0.01), IL-6 (P < 0.001), and IL-1 beta (P < 0.01) compared to healthy subjects, with a shift of the dexamethasone dose-response curve to the right. No significant differences in the basal and LPS-stimulated secretion of the three cytokines were observed between CSD and non-CSD patients, and both subgroups of patients had similar degrees of dexamethasone-mediated cytokine inhibition. We conclude that patients with Crohn's disease have a significant decrease in the corticosensitivity of their leukocytes. This may be related to a specific genetic/constitutional background and/or could be acquired, due to inflammation-related endocrine and/or immune factors