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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 hallmarks of the sick euthyroid syndrome or non-thyroidal illness is a decrease of serum triiodothyronine, caused mainly by a decrease in liver deiodinase type 1 (D1) mRNA and activity. Proinflammatory cytokines like interleukin (IL)-1ß are likely involved in this disease, but are also known to inhibit thyroid hormone receptor (TR)-ß1 gene expression, which is of interest as the D1 promoter contains TREs. The aim of the present study was to evaluate whether the IL-1ß-induced decrease of D1 and TRß1 mRNA is mediated by the same cytokine signalling pathways in a human hepatoma cell line (HepG2). We observed a downregulation of both D1 and TRß1 mRNA after 4 h of incubating the cells with IL-1ß. Sulfasalazine was used to inhibit the nuclear factor-B (NFB) pathway and SP600125, a chemical inhibitor of the c-Jun N-terminal kinase, was used as an inhibitor of the activator protein-1 (AP-1) pathway. AP-1 inhibition did not affect the decrease of D1 and TRß1 mRNA, but the TRß1 mRNA decrease was completely abolished after inhibiting NFB, while D1 mRNA was unaffected. Only simultaneous inhibition of both the NFB and AP-1 pathways abolished the D1 mRNA decrease. We concluded that IL-1ß stimulation of HepG2 cells results in a marked decrease of D1 and TRß1 mRNA. The decrease of TRß1 mRNA is exclusively mediated by the NFB pathway, while the decrease of D1 mRNA requires inhibition of both the AP-1 and the NFB pathways.

This article has been cited by other articles:

				J Kwakkel, O Chassande, H C van Beeren, W M Wiersinga, and A Boelen Lacking thyroid hormone receptor {beta} gene does not influence alterations in peripheral thyroid hormone metabolism during acute illness J. Endocrinol., April 1, 2008; 197(1): 151 - 158. [Abstract] [Full Text] [PDF]

				J Kwakkel, W M Wiersinga, and A Boelen Interleukin-1{beta} modulates endogenous thyroid hormone receptor {alpha} gene transcription in liver cells J. Endocrinol., August 1, 2007; 194(2): 257 - 265. [Abstract] [Full Text] [PDF]