Changes in gene expression of DOR and other thyroid hormone receptors in rat liver during acute-phase response

Non-thyroidal illness is characterized by low triiodothyronine (T3) serum level under acute-phase conditions. We studied hepatic gene expression of the newly identified thyroid hormone receptor (TR) cofactor DOR/TP53INP2 together with TRs in a rat model of aseptic abscesses induced by injecting intramuscular turpentine-oil into each hind limb. A fast (4-6 h) decrease in the serum level of free thyroxine and free T3 was observed. By immunohistology, abundant DOR protein expression was detected in the nuclei of hepatocytes and ED-1(+) (mononuclear phagocytes), CK-19(+) (biliary cells), and SMA(+) (mesenchymal cells of the portal tract) cells. DOR signal was reduced with a minimum at 6-12 h after the acute-phase reaction (APR). Immunohistology also showed a similar pattern of protein expression in TR alpha 1 but without a significant change during APR. Transcripts specific for DOR, nuclear receptor corepressor 1 (NCoR-1), and TR beta 1 were down-regulated with a minimum at 6-12 h, whereas expression for TR alpha 1 and TR alpha 2 was slightly and significantly up-regulated, respectively, with a maximum at 24 h after APR was initiated. In cultured hepatocytes, acute-phase cytokines interleukin-1 beta (1L-1 beta) and IL-6 down-regulated DOR and TR beta 1 at the mRNA level. Moreover, gene expression of DOR and TRs (TR alpha 1, TR alpha 2, and TR beta 1) was up-regulated in hepatocytes by adding 13 to the culture medium; this upregulation was almost completely blocked by treating the cells with IL-6. Thus, TR beta 1, NCoR-1, and the recently identified DOR/TP53INP2 are abundantly expressed and down-regulated in liver cells during APR. Their downregulation is attributable to the decreased serum level of thyroid hormones and most probably also to the direct action of the main acute-phase cytokines.