LPS affects the Thyroid
LPS seems to affect Thyroid Function in very dramatic ways. Not only
does it lower the thyroid levels but it also reduces thyroid hormone
receptor (TR) expression. Furthermore, LPS plays an important part in creating autoimmune thyroiditis as well as goiter.
Below are experiments to demonstrate how LPS lowers thyroid levels with both mice and
Intravenous administration of low-dose endotoxin (lipopolysaccharide, LPS) to healthy subjects reproduced a number of changes in the plasma concentrations of thyroid hormones and TSH commonly seen in NTI, including reduced T4, T3, and TSH concentrations, and increased rT3 levels.
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1: Am J Physiol. 1999 Feb;276(2 Pt 2):R357-62.
Neutralization of TNF does not influence endotoxininduced changes in thyroid hormone metabolism in humans.
van der Poll T, Endert E, Coyle SM, Agosti JM, Lowry SF.
Division of Surgical Sciences, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08903, USA.
To determine the role of tumor necrosis factor (TNF) in endotoxin-induced changes in plasma thyroid hormone and thyroid-stimulating hormone (TSH) concentrations, 24 healthy postabsorptive humans were studied on a control study day (n = 6), after infusion of a recombinant TNF receptor IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) after intravenous injection of endotoxin (2 ng/kg; n = 6), or after administration of endotoxin with TNFR:Fc (n = 6). Administration of TNFR:Fc alone did not affect thyroid hormone or TSH levels when compared with the control day. Endotoxin induced a transient rise in plasma TNF activity (1.5 h: 219 +/- 42 pg/ml), which was completely prevented by TNFR:Fc (P < 0.05). After endotoxin administration, plasma L-thyroxine (T4), free T4, 3,5, 3'-triiodothyronine (T3), and TSH were lower and 3,3', 5'-triiodothyronine was higher than on the control day (all P < 0. 05). Coinfusion of TNFR:Fc with endotoxin did not influence these endotoxin-induced changes. Our results suggest that endogenous TNF does not play an important role in the alterations in plasma thyroid hormone and TSH concentrations induced by mild endotoxemia in healthy humans.
PMID: 9950912 [PubMed - indexed for MEDLINE]
Note: 3,3', 5'-triiodothyronine is rT3
View this article in PubMed
1: J Clin Endocrinol Metab. 1995 Apr;80(4):1341-6.
Interleukin-1 receptor blockade does not affect endotoxin-induced changes in plasma thyroid hormone and thyrotropin concentrations in man.
van der Poll T, Van Zee KJ, Endert E, Coyle SM, Stiles DM, Pribble JP, Catalano MA, Moldawer LL, Lowry SF.
Department of Surgery, Cornell University Medical College, New York, New York 10021, USA.
Interleukin-1 (IL-1) has been implicated as a mediator of the euthyroid sick syndrome. The effects of IL-1 can be blocked by the naturally occurring IL-1 receptor antagonist (IL-1ra). In the present study, iv administration of endotoxin was used as a human model of the euthyroid sick syndrome. To assess the role of endogenous IL-1 in endotoxin-induced changes in plasma thyroid hormone and TSH concentrations, 18 healthy postabsorptive humans were studied on a control study day, followed 3 days later by a study day on which they were randomly assigned to one of three treatments: a 6-h infusion of recombinant human IL-1ra alone (133 mg/h), endotoxin alone (lot EC-5; 20 U/kg), or both endotoxin and IL-1ra. Administration of IL-1ra alone did not affect the plasma concentrations of thyroid hormones or TSH compared with those on the control day. Endotoxin injection was associated with decreases in T4 (P = 0.06 vs. the control day), free T4 (P = 0.02), T3 (P < 0.001), and TSH (P < 0.0001) and a rise in rT3 (P < 0.001), reproducing the major features of the euthyroid sick syndrome. Coinfusion of IL-1ra did not influence these endotoxin-induced changes. Our results suggest that endogenous IL-1 does not play an important role in the alterations in plasma thyroid hormone and TSH concentrations induced by mild endotoxemia in healthy humans.
PMID: 7714108 [PubMed - indexed for MEDLINE]
Clarification of the meaning of "endotoxin alone (lot EC-5; 20 U/kg)" is provided by an another article written by the same author:
View this article.
Inside that article is the following quote that shows that endotoxin (lot EC-5)
refers to LPS from Escherichia coli.
"Twelve subjects received an intravenous injection with LPS [National Reference Endotoxin, Escherichia coli 0113 (lot EC-5), generously provided by Dr. H. D. Hochstein, the Bureau of Biologics, Food and Drug Administration, Bethesda, MD]"
LPS lowering the thyroid levels of mice:
European Journal of Endocrinology, Vol 151, Issue 4, 497-502
Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis
A Boelen, J Kwakkel, M Platvoet-ter Schiphorst, B Mentrup, A Baur, J Koehrle, and WM Wiersinga
Department of Endocrinology, Academic Medical Center, University of Amsterdam, The Netherlands. email@example.com
OBJECTIVE: Proinflammatory cytokines are involved in the pathogenesis of non-thyroidal illness (NTI), as shown by studies with IL-6-/- and IL-12-/- mice. Interleukin (IL)-6 changes peripheral thyroid hormone metabolism, and IL-12 seems to be involved in the regulation of the central part of the hypothalamic-pituitary-thyroid (HPT) axis during illness. IL-18 is a proinflammatory cytokine which shares important biological properties with IL-12, such as interferon (IFN)-gamma-inducing activity. DESIGN: By studying the changes in the HPT-axis during bacterial lipopolysaccharide (LPS)-induced illness in IL-18-/-, IFNgammaR-/- and wild-type (WT) mice, we wanted to unravel the putative role of IL-18 and IFNgamma in the pathogenesis of NTI. RESULTS: LPS induced a decrease in pituitary type 1 deiodinase (D1) activity (P<0.05, ANOVA) in WT mice, but not in IL-18-/- mice, while the decrease in D2 activity was similar in both strains.
LPS decreased serum thyroid hormone levels and liver D1 mRNA within 24 h similarly in IL-18-/-, and WT mice. The expression of IL-1, IL-6 and IFNgamma mRNA expression was significantly lower in IL-18-/- mice than in WT, while IL-12 mRNA expression was similar. IFNgammaR-/- mice had higher basal D1 activity in the pituitary than WT mice (P<0.05); LPS induced a decrease of D2, but not of D1, activity in the pituitary which was similar in both strains. In the liver, the LPS-induced increase in cytokine expression was not different between IFNgammaR-/- mice and WT mice, and the decrease in serum T3 and T4 levels and hepatic D1 mRNA was also similar. CONCLUSIONS: The relative decrease in serum T3 and T4 and liver D1 mRNA in response to LPS is similar in IL-18-/-, IFNgammaR-/- and WT mice despite significant changes in hepatic cytokine induction. However, the LPS-induced decrease in D1 activity in the pituitary of WT mice is absent in IL-18-/- mice; in contrast, LPS did not decrease pituitary D1 activity in the IFNgammaR-/- mice or their WT, which might be due to the genetic background of the mice. Our results suggest that IL-18 is also involved in the regulation of the central part of the HPT axis during illness.
The article below demonstrates that bacterial infection also reduces thyroid hormone receptor (TR) expression.
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1: Am J Physiol Endocrinol Metab. 2003 Jan;284(1):E228-36. Epub 2002 Sep 3.
Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver.
* Beigneux AP,
* Moser AH,
* Shigenaga JK,
* Grunfeld C,
* Feingold KR.
Department of Medicine, University of California San Francisco, 94121, USA. firstname.lastname@example.org
Infection is associated with low serum thyroid hormones and thyrotropin levels. Here we demonstrate that infection also reduces thyroid hormone receptor (TR) expression. In gel shift experiments, retinoid X receptor (RXR)/TR DNA binding was reduced in mouse liver by 60 and 77%, respectively, 4 and 16 h after lipopolysaccharide (LPS) administration. Surprisingly, LPS did not decrease either TR-alpha or TR-beta protein levels at 4 h, but by 16 h TR-alpha(1), TR-alpha(2), and TR-beta levels were reduced by 55, 87, and 41%, respectively. We previously reported that LPS rapidly decreases RXR protein levels in liver. Therefore, we added RXR-beta to hepatic nuclear extracts prepared 4 h after LPS treatment, which restored RXR/TR DNA binding to a level comparable to that of controls. A similar experiment conducted on extracts prepared 16 h after LPS administration did not restore RXR/TR DNA binding. We propose that decreased RXR expression is limiting for RXR/TR DNA binding at 4 h, whereas the reduction in both TR and RXR levels results in further decreased binding at 16 h.
PMID: 12388159 [PubMed - indexed for MEDLINE]
LPS is also associated with thyroid immune disorders such as Hashimoto and goiter.
To read more about thyroid and LPS.