title: NFκB signaling is essential for the lipopolysaccharide-induced increase of type 2 deiodinase in tanycytes.
abstract: The enzyme type 2 deiodinase (D2) is a major determinant of T₃ production in the central nervous system. It is highly expressed in tanycytes, a specialized cell type lining the wall of the third ventricle. During acute inflammation, the expression of D2 in tanycytes is up-regulated by a mechanism that is poorly understood at present, but we hypothesized that cJun N-terminal kinase 1 (JNK1) and v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) (the 65 kD subunit of NFκB) inflammatory signal transduction pathways are involved. In a mouse model for acute inflammation, we studied the effects of lipopolysaccharide (LPS) on mRNA expression of D2, JNK1, and RelA in the periventricular area (PE) and the arcuate nucleus-median eminence of the hypothalamus. We next investigated LPS-induced D2 expression in primary tanycyte cell cultures. In the PE, the expression of D2 was increased by LPS. In the arcuate nucleus, but not in the PE, we found increased RelA mRNA expression. Likewise, LPS increased D2 and RelA mRNA expression in primary tanycyte cell cultures, whereas JNK1 mRNA expression did not change. Phosphorylation of RelA and JNK1 was increased in tanycyte cell cultures 15-60 minutes after LPS stimulation, confirming activation of these pathways. Finally, inhibition of RelA with the chemical inhibitors sulfasalazine and 4-Methyl-N¹-(3-phenylpropyl)benzene-1,2-diamine (JSH-23) in tanycyte cell cultures prevented the LPS-induced D2 increase. We conclude that NFκB signaling is essential for the up-regulation of D2 in tanycytes during inflammation.
authors.affiliation: Department of Endocrinology and Metabolism (E.M.V., J.K., L.E., A.K., E.F., A.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Rowett Institute for Nutrition and Health (P.B.), University of Aberdeen, Aberdeen AB21 9SB, United Kingdom; and Hypothalamic Integration Mechanisms (A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: de Vries
authors.forename: J
authors.initials: J
authors.lastname: Kwakkel
authors.forename: L
authors.initials: L
authors.lastname: Eggels
authors.forename: A
authors.initials: A
authors.lastname: Kalsbeek
authors.forename: P
authors.initials: P
authors.lastname: Barrett
authors.forename: E
authors.initials: E
authors.lastname: Fliers
authors.forename: A
authors.initials: A
authors.lastname: Boelen
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004731:Endotoxins / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects*; D063928:Ependymoglial Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005260:Female; D007453:Iodide Peroxidase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008473:Median Eminence / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D020644:Midline Thalamic Nuclei / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D004731:Endotoxins; D007453:Iodide Peroxidase; D048055:Mitogen-Activated Protein Kinase 8; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D051996:Transcription Factor RelA; D000097564:Iodothyronine Deiodinase Type II; C044101:endotoxin, Escherichia coli