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Introduction Nonthyroidal illness syndrome (NTIS), also known as low T3 syndrome, is a clinical condition observed in ill patients characterized by a rapid decrease in serum triiodothyronine (T3) levels accompanied by increased reverse T3 (rT3
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, collectively known as the nonthyroidal illness syndrome (NTIS), remains incompletely understood. Although the prevailing view was that NTIS results in overall downregulation of metabolism to save energy, recent work has shown a more complex picture ( Boelen et
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Introduction Illness results in profound changes in thyroid hormone (TH) metabolism called the ‘sick euthyroid syndrome’ or ‘nonthyroidal illness syndrome’ (NTIS). NTIS is characterized by decreased serum triiodothyronine (T 3 ) and thyroxine (T 4
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Introduction Acute systemic illness induced by bacterial endotoxin (lipopoly saccharide; LPS) administration, results in altered peripheral and central thyroid hormone metabolism, so-called nonthyroidal illness (NTI; Papanicolaou
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Department of Endocrinology and Metabolism, Hypothalamic Integration Mechanisms, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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Introduction Profound changes occur in the hypothalamus–pituitary–thyroid (HPT) axis during illness and starvation. The nonthyroidal illness syndrome (NTIS) is characterized by decreased serum tri-iodothyronine (T 3 ) and thyroxine (T 4
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Introduction Increased serum levels of proinflammatory cytokines have been associated with nonthyroidal illness (NTI; Boelen et al. 1993 ), which is a state of altered thyroid hormone regulation and metabolism during illness
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The c-erbAalpha gene encodes two thyroid hormone receptors, TRalpha1 and TRalpha2, that arise from alternative splicing of the TRalpha pre-mRNA. TRalpha2 is not able to bind triiodothyronine (T(3)) and acts as a weak antagonist of TRs. It has been suggested that the balance of TRalpha1 to TRalpha2 is important in maintaining homeostasis. Here, we study the effect of thyroid hormone on the splicing of TRalpha under various conditions in HepG2 cells. First, T(3) was added to HepG2 cells that endogenously express TRalpha. This resulted in a decrease in the TRalpha1:TRalpha2 mRNA ratio after the addition of 10(-)(8 )M or 10(-)(7 )M T(3). Then, HepG2 cells were incubated with sera from hypothyroid or hyperthyroid patients. Sera from hyperthyroid patients (n=6) decreased the TRalpha1:TRalpha2 ratio compared with HepG2 cells incubated with sera from euthyroid patients (n=8). Sera from hypothyroid patients (n=6) had no effect on the TRalpha1:TRalpha2 ratio but supplementation with T(3) caused a decrease in the ratio. Finally, we tested sera from patients with nonthyroidal illness (NTI; n=17) which showed no effect on TRalpha splicing when compared with controls. Free thyroxine levels in sera from hypo-, eu-, and hyperthyroid patients, but not that of NTI patients, were negatively correlated (P<0.01) to the TRalpha1:TRalpha2 ratio. We next studied the expression of the splicing factors hnRNP A1 and ASF/SF2 (SF2) in relation to the splicing of the TRalpha gene. In HepG2 cells incubated with NTI sera a negative relationship was found between the ratio of hnRNP A1:SF2 and the TRalpha1:TRalpha2 ratio. A high hnRNP A1:SF2 ratio is associated with the use of the distal 5'-splice site. The splicing direction should then change towards TRalpha2, which is indeed the case. Rev-ErbA, which is partly complementary to TRalpha2 and could therefore interfere in the splicing process, did not relate to the TRalpha1:TRalpha2 ratio.In conclusion, high T(3) levels induce a low TRalpha1:TRalpha2 ratio which could protect the cell from excessive T(3)-induced gene expression. In vivo, this might be a mechanism to keep tIssues relatively euthyroid during high serum T(3) levels.
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any specific grant from any funding agency in the public, commercial or not-for-profit sector. References Adriaanse R Romijn JA Brabant G Endert E Wiersinga WM 1993 Pulsatile thyrotropin secretion in nonthyroidal illness . Journal of
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of the increased serum interleukin-6 concentration to changes of thyroid function in nonthyroidal illness . Journal of Endocrinological Investigation 17 269 – 274 . ( doi:10.1007/BF03348974 ) Bello G Ceaichisciuc I Silva S Antonelli M
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Wiersinga WM Kohrle J 2006b Contributions of cytokines to nonthyroidal illness . Current Opinion in Endocrinology and Diabetes 13 444 – 450 (Ref type: Journal (Full)) . Boelen A Boorsma J Kwakkel J Wieland CW Renckens R Visser TJ
