HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Kwakkel, J Articles by Boelen, A Search for Related Content PubMed PubMed Citation Articles by Kwakkel, J Articles by Boelen, A

Department of Endocrinology and Metabolism, Academic Medical Center F5-165, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

(Requests for offprints should be addressed to J Kwakkel; Email: g.j.kwakkel{at}amc.uva.nl)

One of the main characteristics of nonthyroidal illness (NTI) is a decrease in serum triiodothyronine, partly caused by a decrease in liver deiodinase type 1 (D1) mRNA and activity. Proinflammatory cytokines have been associated with NTI in view of their capability to decrease D1 and thyroid hormone receptor (TR)ß1 mRNA expression in hepatoma cells. Proinflammatory cytokine induction leads to activation of the inflammatory pathways nuclear factor (NF)B and activator protein (AP)-1. The proinflammatory cytokine interleukin (IL)-1ß decreases thyroid hormone receptor (TR)ß1 mRNA in an NFB-dependent way. The aim of this study was to unravel the effects of IL-1ß on endogenous TR gene expression in an animal model and in a liver cell line. The TR gene product is alternatively spliced in TR1 and TR2, TR2 is capable of inhibiting TR1-induced gene transcription. We showed that both TR1 and TR2 mRNA decreased not only after lipopolysaccharide administration in liver of mice, but also after IL-1ß stimulation of hepatoma cells (HepG2). Using the NFB inhibitor sulfasalazine and the AP-1 inhibitor SP600125, it became clear that the IL-1ß-induced decrease in TR mRNA expression in HepG2 cells can only be abolished by simultaneous inhibition of NFB and AP-1. The IL-1ß-induced TR1 and TR2 mRNA decrease in HepG2 cells is the result of decreased TR gene promoter activity, as evident from actinomycin D experiments. Cycloheximide experiments showed that the decreased promoter activity is independent of de novo protein synthesis and therefore most likely due to posttranslational modifications such as phosphorylation or subcellular relocalization.