Contribution of TNF-α and Nuclear Factor-κB Signaling to Type 2 Iodothyronine Deiodinase Activation in the Mediobasal Hypothalamus after Lipopolysaccharide Administration

• Published in: Endocrinology (Philadelphia) 2010-08, Vol.151 (8), p.3827-3835
• Main Authors: Sánchez, Edith, Singru, Praful S, Wittmann, Gábor, Nouriel, Shira S, Barrett, Perry, Fekete, Csaba, Lechan, Ronald M
• Format: Article
• Language: English
• Subjects: Body weight; Cyclic AMP response element-binding protein; Delayed response; Gene expression; Hypothalamus; Iodide peroxidase; Lipopolysaccharides; Phosphorylation; Pituitary; Polyethylene glycol; Tanycytes; Thyroxine deiodinase; Tumor necrosis factor receptors; Tumor necrosis factor-α; Ventricles (cerebral)
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-0279

To determine whether signaling through TNF and/or nuclear factor-κB contributes to bacterial lipopolysaccharide (LPS)-induced activation of type 2 iodothyronine deiodinase (D2) in tanycytes lining the floor and infralateral walls of the third ventricle, the effect of a TNF antagonist on D2 gene expression and LPS-induced Iκ-Bα expression in tanycytes were studied. Animals treated with soluble, rat, polyethylene glycol-conjugated TNF receptor type 1 (4 mg/kg body weight) before a single ip injection of LPS showed a significant reduction in circulating IL-6 levels but no effect on LPS-induced D2 mRNA in the majority of tanycytes with the exception of a subpopulation of α tanycytes in the wall of the third ventricle. LPS induced a rapid increase in Iκ-Bα mRNA in the pars tuberalis and a delayed response in α tanycytes but absent in all other tanycyte subsets. The LPS-induced increase in Iκ-Bα in the pars tuberalis was associated with increased TSHβ gene expression in this tissue, but cAMP response element-binding protein (CREB) phosphorylation was observed only in a subset of α tanycytes. These data suggest that TNF and nuclear factor-κB signaling are not the primary, initiating mechanisms mediating the LPS-induced D2 response in tanycytes, but may contribute in part to sustaining the LPS-induced D2 response in a subset of α tanycytes. We hypothesize that in addition to TSH, other factors derived from the pars tuberalis may contribute to LPS-induced D2 activation in tanycytes. D2 expressed in tanycytes is highly regulated in response to bacterial LPS and may contribute to central hypothyroidism associated with infection.