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Title: MICROARRAY ANALYSIS REVEALS INTERLEUKIN-6 AS A NOVEL SECRETORY PRODUCT OF THE HYPOTHALAMO-NEUROHYPOPHYSEAL.

Author
item GHORBEL, MOHAMED - UNIVERSITY OF BRISTOL, UK
item SHARMAN, GREIG - UNIVERSITY OF BRISTOL, UK
item LEROUX, MARIE - UNIVERSITY OF BRISTOL, UK
item BARRETT, TANYA - NIH
item Donovan, David
item BECKER, KEVIN - NIH
item MURPHY, DAVID - UNIVERSITY OF BRISTOL, UK

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/3/2003
Publication Date: 5/23/2003
Citation: Ghorbel, M.T., Sharman, G., Leroux, M., Barrett, T., Donovan, D.M., Becker, K.G., Murphy, D. Microarray analysis reveals interleukin-6 as a novel secretory product of the hypothalamo-neurohypophyseal.. Journal of Biological Chemistry.2003 MAY 23; 278(21):19280-5. EPUB 2003 MARCH 14

Interpretive Summary: There are many unanswered questions regarding the cytokines and hormones involved in the complex physiology of mammalian systems. The work presented here uses rat as a mammalian model system, to examine the mammalian response to dehydration. The parts of the pituitary gland and brain that are involved, and at least one hormone/neurotransmitter (vasopressin) are all known from previous work. In order to identify new candidate genes, total RNA was isolated from the pertinent pituitary gland and brain regions from untreated control rats and rats that had undergone dehydration. Altered gene expression resulting from the dehydration is reflected in differences in abundance of specific gene transcripts from the control versus treated animals. cDNA microarray was used to discern changes in gene expression, between the control vs dehydrated rats. Microarray analysis revealed nine candidate genes strongly upregulated in the dehydrated animals. One interesting gene encoded the cytokine IL-6. This result was further documented with in situ hybridization , immunocytochemistry, and western blotting. By examining the tissues involved and the patterns of expression, the major finding of this work is that IL-6 and vasopressin follow the same secretory pathway during this process, with both originating in the pituitary gland.

Technical Abstract: Physiological activation of the hypothalamo-neurohypophyseal system (HNS) by dehydration results is a massive release of vasopressin (VP) from the posterior pituitary. This is accompanied by a functional remodeling of the HNS. In this study we used cDNA arrays in an attempt to identify genes that exhibit differential expression in the hypothalamus following dehydration. Our study revealed nine candidate genes, including interleukin-6 (IL-6) as a putative novel secretory product of HNS worthy of further analysis. In situ hybridization and immunocytochemistry confirmed that IL-6 is robustly expressed in the supraoptic (SON) and the paraventricular (PVN) nuclei of the hypothalamus. By double staining immunofluorescence we showed that IL-6 is largely co-localized with VP in the SON and PVN. In situ hybridization, immunocytochemistry, and Western blotting all revealed IL-6 up-regulation in the SON and PVN following dehydration, thus validating the array data. The same dehydration stimulus resulted in an increase in IL-6 immunoreactivity in the axons of the internal zone of the median eminence and a marked reduction in IL-6-like material in the posterior pituitary gland. We thus suggest that IL-6 takes the same secretory pathway as VP and is secreted from the posterior pituitary following a physiological stimulus.