Contribution of TNF-alpha and nuclear factor-kappaB signaling to type 2 iodothyronine deiodinase activation in the mediobasal hypothalamus after lipopolysaccharide administration.
To determine whether signaling through TNF and/or nuclear factor-kappaB 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 Ikappa-Balpha 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 alpha tanycytes in the wall of the third ventricle. LPS induced a rapid increase in Ikappa-Balpha mRNA in the pars tuberalis and a delayed response in alpha tanycytes but absent in all other tanycyte subsets. The LPS-induced increase in Ikappa-Balpha in the pars tuberalis was associated with increased TSHbeta gene expression in this tissue, but cAMP response element-binding protein (CREB) phosphorylation was observed only in a subset of alpha tanycytes. These data suggest that TNF and nuclear factor-kappaB 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 alpha tanycytes. We hypothesize that in addition to TSH, other factors derived from the pars tuberalis may contribute to LPS-induced D2 activation in tanycytes.
Sánchez
Edith
E
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, Massachusetts 02111, USA.
Singru
Praful S
PS
Wittmann
Gábor
G
Nouriel
Shira S
SS
Barrett
Perry
P
Fekete
Csaba
C
Lechan
Ronald M
RM
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007107:Immune System / Q000187:drug effects / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013972:Thyrotropin / Q000235:genetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*; D000097564:Iodothyronine Deiodinase Type II
D017362:Cyclic AMP Response Element-Binding Protein; D020672:I-kappa B Proteins; D007453:Iodide Peroxidase; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013972:Thyrotropin; D014409:Tumor Necrosis Factor-alpha; D000097564:Iodothyronine Deiodinase Type II