Evidence that down regulation of hypothalamic KiSS-1 expression is involved in the negative feedback action of testosterone to regulate luteinising hormone secretion in the adult male rhesus monkey (Macaca mulatta).

In the male monkey, luteinising hormone (LH) secretion is regulated by a negative feedback action of testicular testosterone that is exerted indirectly at the hypothalamic level to decelerate pulsatile gonadotrophin-releasing hormone release (GnRH). The purpose of the present experiment was to investigate whether the kisspeptin-G protein-coupled receptor 54 (GPR54) signalling pathway is involved in mediating the action of testosterone to suppress GnRH release in the monkey, as has been indicated by studies of nonprimates. To this end, 12 castrated adult male rhesus monkeys were implanted with either testosterone containing or empty Silastic capsules. Testosterone treatment produced a square wave increment in circulating testosterone levels within the physiologic range. After suppression of LH and follicle-stimulating hormone secretion was established at 5-6 weeks of testosterone exposure, the animals were killed and expression of the genes encoding for kisspeptin, GPR54 and GnRH determined in the mediobasal hypothalamus and preoptic area of both treated and control animals using RNase protection assays. The suppression in pituitary gonadotrophin secretion was associated with a reduction in kisspeptin mRNA levels in the mediobasal hypothalamus, but not the preoptic area. GPR54 mRNA levels, on the other hand, were not influenced by testosterone treatment. These results are consistent with those previously reported for the rodent, and suggest that the neurobiology of the negative feedback action of testicular testosterone on LH secretion in the monkey, a representative higher primate, may be mediated by kisspeptinergic neurones upstream to the GnRH network.

alpha-Interferon-induced transcription of HLA and metallothionein genes containing homologous upstream sequences.

Complementary DNAs corresponding to the interferon (IFN)-induced messenger RNAs for histocompatibility locus antigens (HLA), metallothionein-II (MT2), 2',5'-oligoadenylate synthetase and about eight other proteins of unknown sequence have been isolated recently, and by interferon regulation of transcription has been demonstrated for several of the eight mRNAs, with a significant increase apparent in as little as 5 min. We now show that IFN-alpha treatment results in a three- to fivefold increase in the transcription of MT2 and HLA class I genes in human T98G neuroblastoma cells. Furthermore, comparison of regions upstream of the MT2A gene, two HLA genes and one HLA class II gene reveals a homologous sequence of approximately 30 base pairs (bp) which may be involved in regulating transcription of interferon-induced genes. Transcription of the mRNA for human MT2A is induced by glucocorticoids or metal ions and the regulatory elements have been mapped by promoter-fusion experiments. We now show that the rate of transcription of MT2A is the same on treatment with interferon or dexamethasone, but that the mRNA accumulates much faster with dexamethasone, indicating that post-transcriptional events are important in the latter case.