Interleukin-1 beta modulates endogenous thyroid hormone receptor alpha gene transcription in liver cells

One of the main characteristics of nonthyroidal illness (NTI) is a decrease in serum tri-iodothyronine, 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]:)I and thyroid hormone receptor (TR)beta 1 mRNA expression in hepatoma cells. Proinflammatory cytokine induction leads to activation of the inflammatory pathways nuclear factor (NF)kappa B and activator protein (AP)-1. The proinflammatory cytokine interleukin decreases thyroid hormone receptor (TR)beta 1 mRNA in an NF kappa B-dependent way. The aim of this Study was to unravel the effects of IL-1 beta on endogenous TR alpha gene expression in an animal model and in a liver cell line. The TR alpha gene product is alternatively spliced in TR alpha 1 and TR alpha 2, TR alpha 2 is capable of inhibiting TR alpha 1-induced gene transcription. We showed that both TR alpha 1 and TR alpha 2 mRNA decreased not only after lipopolysaccharide administration in liver of mice, but also after IL-1 beta stimulation of hepatoma cells (HepG2). Using the NF kappa B inhibitor sulfasalazine and the AP-1 inhibitor SP600125, it became clear that the IL-1 beta-induced decrease in TR alpha mRNA expression in HepG2 cells can only be abolished by simultaneous inhibition of NF kappa B and AP-1. The IL-1 beta-induced TR alpha 1 and TR alpha 2 mRNA decrease in HepG2 cells is the result of decreased TR alpha gene promoter activity, as evident from actinomycin D experiments. Cycloheximide experiments showed that the decreased promoter activity is independent of dc novo protein synthesis and therefore most likely due to posttranslational modifications such as phosphorylation or subcellular relocalization