Characterization of the nuclear factor-κB responsiveness of the human dio2 gene

Anikó Zeöld, Márton Doleschall, Michael C. Haffner, Luciane P. Capelo, Judit Menyhért, Zsolt Liposits, Wagner S. Da Silva, Antonio C. Bianco, Imre Kacskovics, Csaba Fekete, Balázs Gereben

Research output: Article

55 Citations (Scopus)

Abstract

Type 2 iodothyronine deiodinase (D2) activates T4 by deiodination to T3, a process being the source of most T3 present in the brain. In the mediobasal hypothalamus, expression of the dio2 gene is potently activated by administration of bacterial lipopolysaccharide (LPS), which in turn mediates the modifications in thyroid homeostasis typically observed in patients with nonthyroidal illness syndrome. Here we show that LPS-induced D2 expression is also observed in human MSTO-211H cells that endogenously express D2. Exposure to LPS rapidly doubled D2 activity by a mechanism that was partially blocked by the nuclear factor-κB (NF-κB) inhibitor sulfasalazine. Next, the human dio2 5′-flanking region promoter assay was used in HC11 cells and the p65/NF-κB responsiveness mapped to the 3′ approximately 600-bp region of hdio2 5′-flanking region, with an approximately 15-fold induction. Semiquantitative EMSA identified the strongest NF-κB binding sites at the positions -683 bp (called no. 2) and -198 bp (no. 5) 5′ to the transcriptional starting site. Despite the very similar NF-κB binding affinity of these two sites, site-directed mutagenesis and promoter assay indicated that only site no. 5 possessed transactivation potency in the presence of the p65 subunit of NF-κB. Other cytokine mediators such as signal transducer and activator of transcription-3 (STAT3) or signal transducer and activator of transcription-5 (STAT5) did not induce transcription of the dio2 gene. Our results indicate that inflammatory signals regulate D2 expression predominantly via the NF-κB pathway in a direct transcriptional manner and could contribute to the changes in thyroid economy observed in nonthyroidal illness syndrome during infection.

Original languageEnglish
Pages (from-to)4419-4429
Number of pages11
JournalEndocrinology
Volume147
Issue number9
DOIs
Publication statusPublished - 2006

ASJC Scopus subject areas

  • Endocrinology

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    Zeöld, A., Doleschall, M., Haffner, M. C., Capelo, L. P., Menyhért, J., Liposits, Z., Da Silva, W. S., Bianco, A. C., Kacskovics, I., Fekete, C., & Gereben, B. (2006). Characterization of the nuclear factor-κB responsiveness of the human dio2 gene. Endocrinology, 147(9), 4419-4429. https://doi.org/10.1210/en.2005-1608