Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: Implications for the nonthyroidal illness syndrome

Csaba Fekete, Balázs Gereben, Márton Doleschall, John W. Harney, Jose Miguel Dora, Antonio C. Bianco, Sumit Sarkar, Zsolt Liposits, William Rand, Charles Emerson, Imre Kacskovics, P. Reed Larsen, Ronald M. Lechan

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Abstract

To determine whether the type 2 iodothyronine deiodinase (D2), the principal central nervous system enzyme converting T4 to biologically active T3, is regulated in tanycytes by immune activation, D2 activity was measured in the mediobasal hypothalamus (MBH) 4, 12, and 24 h after administration of bacterial lipopolysaccharide (LPS) and compared with D2 levels in the cortex and anterior pituitary of rats. In contrast to D2 activity in the cortex and anterior pituitary that showed a steady linear increase over 24 h, which was coincident with a decline in thyroid hormone and TSH levels, D2 activity peaked in the MBH 12 h after LPS administration. By in situ hybridization, the increased D2 mRNA synthesis induced by LPS was specifically localized to tanycytes lining the third ventricle. In vitro assays in HC11 and HEK-293 cells demonstrated that the p65 subunit of nuclear factor-κB markedly increased both rat and human D2 genes (dio2) as analyzed by promoter assays. No activation of human dio2 was observed when an 83-bp minimal promoter was used. We propose that LPS or LPS-induced cytokines directly induce D2 mRNA in tanycytes. The ensuing MBH-specific D2-mediated local thyrotoxicosis may suppress the hypothalamus-pituitary-thyroid axis by local feedback inhibition of hypophysiotropic TRH and/or TSH and contribute to the mechanism of central hypothyroidism associated with infection.

Original languageEnglish (US)
Pages (from-to)1649-1655
Number of pages7
JournalEndocrinology
Volume145
Issue number4
DOIs
StatePublished - Apr 2004

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ASJC Scopus subject areas

  • Endocrinology

Cite this

Fekete, C., Gereben, B., Doleschall, M., Harney, J. W., Dora, J. M., Bianco, A. C., Sarkar, S., Liposits, Z., Rand, W., Emerson, C., Kacskovics, I., Reed Larsen, P., & Lechan, R. M. (2004). Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: Implications for the nonthyroidal illness syndrome. Endocrinology, 145(4), 1649-1655. https://doi.org/10.1210/en.2003-1439