Differential involvement of nuclear factor-κB and activator protein-1 pathways in the interleukin-1β-mediated decrease of deiodinase type 1 and thyroid hormone receptor β1 mRNA

Abstract

One of the hallmarks of the sick euthyroid syndrome or non-thyroidal illness is a decrease of serum tri-iodothyronine, caused mainly by a decrease in liver deiodinase type 1 (D1) mRNA and activity. Proinflammatory cytokines like interleukin (IL)-1β are likely involved in this disease, but are also known to inhibit thyroid hormone receptor (TR)-β1 gene expression, which is of interest as the D1 promoter contains TREs. The aim of the present study was to evaluate whether the IL-1β-induced decrease of D1 and TRβ1 mRNA is mediated by the same cytokine signalling pathways in a human hepatoma cell line (HepG2). We observed a downregulation of both D1 and TRβ1 mRNA after 4 h of incubating the cells with IL-β1. Sulfasalazine was used to inhibit the nuclear factor-κB (NFκB) 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 TRβ1 mRNA, but the TRβ1 mRNA decrease was completely abolished after inhibiting NFκB, while D1 mRNA was unaffected. Only simultaneous inhibition of both the NFβB and AP-1 pathways abolished the D1 mRNA decrease. We concluded that IL-1β stimulation of HepG2 cells results in a marked decrease of D1 and TRβ1 mRNA. The decrease of TRβ1 mRNA is exclusively mediated by the NFβB pathway, while the decrease of D1 mRNA requires inhibition of both the AP-1 and the NFκB pathways. © 2006 Society for Endocrinology.