Lacking thyroid hormone receptor β gene does not influence alterations in peripheral thyroid hormone metabolism during acute illness

Abstract

The downregulation of liver deiodinase type 1 (D1) is supposed to be one of the mechanisms behind the decrease in serum tri-iodothyronine (T 3 ) observed during non-thyroidal illness (NTI). Liver D1 mRNA expression is positively regulated by T 3 , mainly via the thyroid hormone receptor (TR)b1. One might thus expect that lacking the TRb gene would result in diminished downregulation of liver D1 expression and a smaller decrease in serum T 3 during illness. In this study, we used TRb K/K mice to evaluate the role of TRb in lipopolysaccharide (LPS, a bacterial endotoxin)-induced changes in thyroid hormone metabolism. Our results show that the LPS-induced serum T 3 and thyroxine and liver D1 decrease takes place despite the absence of TRb. Furthermore, we observed basal differences in liver D1 mRNA and activity between TRb K/K and wild-type mice and TRb K/K males and females, which did not result in differences in serum T 3 . Serum T 3 decreased rapidly after LPS administration, followed by decreased liver D1, indicating that the contribution of liver D1 during NTI may be limited with respect to decreased serum T 3 levels. Muscle D2 mRNA did not compensate for the low basal liver D1 observed in TRb K/K mice and increased in response to LPS in TRband WT mice. Other (TRb independent) mechanisms like decreased thyroidal secretion and decreased binding to thyroid hormone-binding proteins probably play a role in the early decrease in serum T 3 observed in this study.

The molecular basis of the non-thyroidal illness syndrome

“…Although it was assumed that mainly the TRb was involved in the illness induced D1 repression in the liver, studies in TRb 0/0 and TRa 0/0 mice show that while the LPS induced D1 decrease is still present in the TRb 0/0 mice, this response is attenuated in the TRa 0/0 mice (Kwakkel et al 2008(Kwakkel et al , 2010. In addition, the IL1b induced decrease in TRb mRNA expression in HepG2 cells is solely dependent on NF-kB signaling, while the decreases in Dio1 and TRa are dependent on both NF-kB and activator protein-1 (AP-1) signaling (Kwakkel et al 2006(Kwakkel et al , 2007.…”

“…Dio2 expression in skeletal muscle increases in intensive-care unit patients (Mebis et al 2007), in several NTIS animal models of acute (Kwakkel et al 2008) and chronic inflammation (Kwakkel et al 2009), while in septic patients and mice muscle Dio2 expression decreases (Rodriguez-Perez et al 2008, Kwakkel et al 2009). The increased Dio2 expression during chronic inflammation is likely due to enhanced CREB signalling (Kwakkel et al 2009), while the decrease during sepsis might be mediated by decreased food intake since 62 h of fasting decreased muscle Dio2 expression in healthy volunteers (Heemstra et al 2009) (see Fig.…”

“…While during acute and chronic inflammation and during sepsis liver Dio3 mRNA expression and activity levels are decreased (Boelen et al 2005(Boelen et al , 2008, hepatic D3 expression and activity are increased in rabbits with prolonged critical illness (Debaveye et al 2005). Slightly increased D3 activity is also observed in the livers of severely ill patients (Peeters et al 2003).…”

“…In addition, peritonitis induced by E. coli and pneumonia induced by S. pneumoniae stimulates D3 expression in infiltrating granulocytes in the liver and lungs respectively (Boelen et al 2008). Granulocytes are part of the innate immune system and have intracellular bacterial killing mechanisms such as the myeloperoxidase (MPO) system (Klebanoff 2005).…”

“…acute illness, induced by administration of a sublethal dose of LPS (Boelen et al 2004a, Fekete et al 2004; chronic inflammation, induced by injection of turpentine in the hind limb ultimately resulting in the formation of an abscess (Chopra et al 1987, Boelen et al 2006; bacterial sepsis, induced by inoculation of Streptococcus pneumoniae or i.p. injection with Escherichia coli (Knapp et al 2003, Boelen et al 2008 and prolonged critical illness in rabbits induced by burn injury (Weekers et al 2002). The similarity between these models is the decrease in serum TH concentrations, although the time course, severity and inflammatory response are variable.…”