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

Abstract

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-1␤ 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. (Endocrinology 141: 606 -614, 2000) T SH COORDINATELY regulates proliferation and differentiated function in thyroid follicular cells. TSH stimulates the expression of thyroid-specific genes, including the TSH receptor (TSHR) (reviewed in Ref. 1), thyroglobulin (Tg) (2-5), thyroid peroxidase (5, 6), iodothyronine 5-deiodinase (7), and the sodium-iodide symporter (8, 9). Cytokines, including interferon-␥ (IFN␥), interleukin-1␤ (IL-1␤), and tumor necrosis factor-␣, are believed to participate in the development and progression of thyroid autoimmunity. IFN␥ increases the autoantigenicity of thyrocytes by upregulating MHC class I expression (10) and by inducing aberrant expression of MHC class II antigens (11-17). Moreover, the expression of several genes under regulatory control by TSH is inhibited by IFN␥. In turn, TSH impairs IFN␥-stimulated Fas expression (18). In addition to opposing effects on gene expression, TSH and IFN␥ exert differential effects on proliferation, where IFN␥ has been shown to inhibit TSH-stimulated proliferation (12,19,20).Thyroid-specific transcription factor-1 (TITF-1; previously termed TTF-1) (21) has been identified as one molecular target of IFN␥ in FRTL-5 cells where IFN␥ decreases TITF-1 DNA-binding activity on the TSHR promoter (22). In human thyroid cells, IFN␥ activates a nuclear protein that binds to the Tg promoter and diminishes Tg expression (23). Given the multitude of the effects of IFN␥ on thyroid cells, it seems likely that there are additional mechan...

Interferon-γ Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2

“…LPL) (28), and a study demonstrating the ability of IFN-␥ to suppress CRE-or the bZIP-containing AP1-regulated promoters (29), and wondered whether this cytokine induces ICER expression. We present here studies that investigate the IFN-␥-ICER link in detail.…”