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Differential Effects of Acute and Chronic Exposure to Interferon- on Cyclic Adenosine 3',5'-Monophosphate Response Element-Regulated Gene Expression¹

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Dr. Judy L. Meinkoth, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084. E-mail: meinkoth{at}pharm.med.upenn.edu

TSH stimulates proliferation and maintains differentiated function in thyroid follicular cells. The mitogenic activity and the stimulatory effects of TSH on thyroid-specific gene expression are impaired by interferon- (IFN); however, the mechanisms for these effects have not been elucidated in detail. We examined the effects of IFN on acute responses to TSH in rat thyroid cells. IFN did not impair TSH-stimulated p70/p85 ribosomal protein S6 kinase (p70/p85s6k) activity or cAMP response element (CRE)-regulated gene expression, although it inhibited DNA synthesis and thyroglobulin expression, effects measured over a more prolonged time course than those on kinase activity and reporter gene expression. Unexpectedly, when cells were chronically exposed to IFN, CRE-lacZ promoter activity was decreased, whereas other cAMP-mediated signals, such as p70/p85s6k activity and CRE-binding protein phosphorylation, were unaffected. Activating protein-1-regulated promoters were also impaired by IFN treatment, but with kinetics that differed from those of CRE-regulated promoters. Neither acute nor chronic treatment with interleukin-1ß impaired cAMP signaling, indicating that the effects of IFN are specific. These studies identify CRE- and activating protein-1-regulated promoters as targets of IFN in thyroid cells and fibroblasts. IFN-mediated inhibition of these promoters, in addition to those containing thyroid-specific transcription factor-1-binding sites, may contribute to the profound effects of IFN on thyroid cells.

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