title: The Role of Hypothalamic NF-κB Signaling in the Response of the HPT-Axis to Acute Inflammation in Female Mice.
abstract: A large proportion of critically ill patients have alterations in the hypothalamus-pituitary-thyroid (HPT) axis, collectively known as the nonthyroidal illness syndrome. Nonthyroidal illness syndrome is characterized by low serum thyroid hormone (TH) concentrations accompanied by a suppressed central component of the HPT axis and persistent low serum TSH. In hypothalamic tanycytes, the expression of type 2 deiodinase (D2) is increased in several animal models of inflammation. Because D2 is a major source of T3 in the brain, this response is thought to suppress TRH expression in the paraventricular nucleus via increased local bioavailability of T3. The inflammatory pathway component RelA (the p65 subunit of nuclear factor-κB) can bind the Dio2 promoter and increases D2 expression after lipopolysaccharide (LPS) stimulation in vitro. We aimed to determine whether RelA signaling in tanycytes is essential for the LPS-induced D2 increase in vivo by conditional elimination of RelA in tanycytes of mice (RelA(ASTKO)). Dio2 and Trh mRNA expression were assessed by quantitative in situ hybridization 8 or 24 hours after saline or LPS injection. At the same time points, we measured pituitary Tshβ mRNA expression and serum T3 and T4 concentrations. In RelA(ASTKO) mice the LPS-induced increase in Dio2 and decrease in Trh mRNA levels in the hypothalamus were reduced compared with the wild-type littermates, whereas the drop in pituitary Tshβ expression and in serum TH concentrations persisted. In conclusion, RelA is essential for the LPS-induced hypothalamic D2 increase and TRH decrease. The central changes in the HPT axis are, however, not required for the down-regulation of Tshβ expression and serum TH concentrations.
authors.affiliation: Department of Endocrinology and Metabolism (E.M.d.V., E.F., A.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Leibniz Institute on Aging-Fritz Lipmann Institute (S.N., R.H., H.H.), 07745 Jena, Germany; Leibniz Research Institute for Environmental Medicine (S.M.S., H.H.), 40225 Düsseldorf, Germany; and Institute of Cellular and Integrative Neurosciences (F.W.P.), University of Strasbourg, 67084 Strasbourg, France.
authors.forename: E M
authors.initials: EM
authors.lastname: de Vries
authors.affiliation: Department of Endocrinology and Metabolism (E.M.d.V., E.F., A.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Leibniz Institute on Aging-Fritz Lipmann Institute (S.N., R.H., H.H.), 07745 Jena, Germany; Leibniz Research Institute for Environmental Medicine (S.M.S., H.H.), 40225 Düsseldorf, Germany; and Institute of Cellular and Integrative Neurosciences (F.W.P.), University of Strasbourg, 67084 Strasbourg, France.
authors.forename: S
authors.initials: S
authors.lastname: Nagel
authors.affiliation: Department of Endocrinology and Metabolism (E.M.d.V., E.F., A.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Leibniz Institute on Aging-Fritz Lipmann Institute (S.N., R.H., H.H.), 07745 Jena, Germany; Leibniz Research Institute for Environmental Medicine (S.M.S., H.H.), 40225 Düsseldorf, Germany; and Institute of Cellular and Integrative Neurosciences (F.W.P.), University of Strasbourg, 67084 Strasbourg, France.
authors.forename: R
authors.initials: R
authors.lastname: Haenold
authors.affiliation: Department of Endocrinology and Metabolism (E.M.d.V., E.F., A.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Leibniz Institute on Aging-Fritz Lipmann Institute (S.N., R.H., H.H.), 07745 Jena, Germany; Leibniz Research Institute for Environmental Medicine (S.M.S., H.H.), 40225 Düsseldorf, Germany; and Institute of Cellular and Integrative Neurosciences (F.W.P.), University of Strasbourg, 67084 Strasbourg, France.
authors.forename: S M
authors.initials: SM
authors.lastname: Sundaram
authors.affiliation: Department of Endocrinology and Metabolism (E.M.d.V., E.F., A.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Leibniz Institute on Aging-Fritz Lipmann Institute (S.N., R.H., H.H.), 07745 Jena, Germany; Leibniz Research Institute for Environmental Medicine (S.M.S., H.H.), 40225 Düsseldorf, Germany; and Institute of Cellular and Integrative Neurosciences (F.W.P.), University of Strasbourg, 67084 Strasbourg, France.
authors.forename: F W
authors.initials: FW
authors.lastname: Pfrieger
authors.affiliation: Department of Endocrinology and Metabolism (E.M.d.V., E.F., A.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Leibniz Institute on Aging-Fritz Lipmann Institute (S.N., R.H., H.H.), 07745 Jena, Germany; Leibniz Research Institute for Environmental Medicine (S.M.S., H.H.), 40225 Düsseldorf, Germany; and Institute of Cellular and Integrative Neurosciences (F.W.P.), University of Strasbourg, 67084 Strasbourg, France.
authors.forename: E
authors.initials: E
authors.lastname: Fliers
authors.affiliation: Department of Endocrinology and Metabolism (E.M.d.V., E.F., A.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Leibniz Institute on Aging-Fritz Lipmann Institute (S.N., R.H., H.H.), 07745 Jena, Germany; Leibniz Research Institute for Environmental Medicine (S.M.S., H.H.), 40225 Düsseldorf, Germany; and Institute of Cellular and Integrative Neurosciences (F.W.P.), University of Strasbourg, 67084 Strasbourg, France.
authors.forename: H
authors.initials: H
authors.lastname: Heuer
authors.affiliation: Department of Endocrinology and Metabolism (E.M.d.V., E.F., A.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Leibniz Institute on Aging-Fritz Lipmann Institute (S.N., R.H., H.H.), 07745 Jena, Germany; Leibniz Research Institute for Environmental Medicine (S.M.S., H.H.), 40225 Düsseldorf, Germany; and Institute of Cellular and Integrative Neurosciences (F.W.P.), University of Strasbourg, 67084 Strasbourg, France.
authors.forename: A
authors.initials: A
authors.lastname: Boelen
mesh_terms: D000818:Animals; D063928:Ependymoglial Cells / Q000378:metabolism; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D010902:Pituitary Gland / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism*; D013963:Thyroid Hormones / Q000097:blood; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D013963:Thyroid Hormones; D013973:Thyrotropin-Releasing Hormone; D007453:Iodide Peroxidase