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Tumor Necrosis Factor- Activates the Human Prolactin Gene Promoter via Nuclear Factor-B Signaling

Endocrine Science Research Group (S.F., M.W., A.D.A., J.R.E.D.), University of Manchester, Manchester M13 9PT, United Kingdom; Centre for Cell Imaging (C.V.H., D.G.S., G.N., M.R.H.W.), School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, United Kingdom; and Molecular Physiology Group (S.S., J.J.M.), University of Edinburgh Medical School, Edinburgh EH16 4TJ, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Prof. Julian Davis, Endocrine Science Research Group School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. E-mail: julian.davis{at}manchester.ac.uk; or Prof. Michael White, School of Biological Sciences, Centre for Cell Imaging, University of Liverpool, Liverpool L69 7ZB, United Kingdom. E-mail: m.white{at}liverpool.ac.uk.

Pituitary function has been shown to be regulated by an increasing number of intrapituitary factors, including cytokines. Here we show that the important cytokine TNF- activates prolactin gene transcription in pituitary GH3 cells stably expressing luciferase under control of 5 kb of the human prolactin promoter. Similar regulation of the endogenous rat prolactin gene by TNF- in GH3 cells was confirmed using real-time PCR. Luminescence microscopy revealed heterogeneous dynamic response patterns of promoter activity in individual cells. In GH3 cells treated with TNF-, Western blot analysis showed rapid inhibitory protein B (IB) degradation and phosphorylation of p65. Confocal microscopy of cells expressing fluorescence-labeled p65 and IB fusion proteins showed transient cytoplasmic-nuclear translocation and subsequent oscillations in p65 localization and confirmed IB degradation. This was associated with increased nuclear factor B (NF-B)-mediated transcription from an NF-B-responsive luciferase reporter construct. Disruption of NF-B signaling by expression of dominant-negative variants of IB kinases or truncated IB abolished TNF- activation of the prolactin promoter, suggesting that this effect was mediated by NF-B. TNF- signaling was found to interact with other endocrine signals to regulate prolactin gene expression and is likely to be a major paracrine modulator of lactotroph function.

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