General Explanation of LPS and the thyroid.

View this article in the American Journal of Physiology Endocrinology and Metabolism.
http://ajpendo.physiology.org/cgi/content/full/284/1/E228

We are quoting a section from the INTRODUCTION of this article:

ACUTE NONTHYROIDAL ILLNESSES, such as infection, inflammation, or trauma, result in what is known as the sick euthyroid syndrome (6, 26, 33). The characteristic feature of this syndrome is low triiodothyronine (T3) plasma levels. If the nonthyroidal illness is severe, low serum thyroxine (T4) levels and an inappropriately low normal to subnormal thyrotropin serum concentration may also occur. The pathogenesis of the sick euthyroid syndrome is poorly understood, but both central (pituitary and hypothalamic) and peripheral defects have been proposed. The central defect manifests itself through a low to normal thyrotropin serum secretion despite low T3 and T4 plasma levels. The most commonly described peripheral defect is the reduced conversion of T4 to T3 because of a decrease in 5'-deiodination in the liver.

Injection of bacterial lipopolysaccharide (LPS), which is known to induce the sick euthyroid syndrome (43), triggers a systemic inflammatory response referred to as the acute-phase response (APR), characterized by alterations in hepatic carbohydrate and lipid metabolism. Hypertriglyceridemia, decreased high-density lipoprotein cholesterol levels, and inhibition of bile acid synthesis are among the alterations in lipid metabolism that occur during the APR (15).

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. a.boelen@amc.uva.nl

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 following article shows patients with sepsis have lower thyroid hormones. Since bacterial infections are the most common cause of sepsis, this article highlights the effect of microbial toxins on thyroid levels.

http://www.clevelandclinic.org/health/health-info/docs/3800/3887.asp?index=12361
What causes sepsis? Bacterial infections are the most common cause of sepsis. Sepsis can also be caused by fungal, parasitic, or viral infections.

View this article in PubMed

1: Intensive Care Med. 1999 Dec;25(12):1402-6.

Activation of the hypothalamo-pituitary-adrenal axis in response to septic or non-septic diseases--implications for the euthyroid sick syndrome.

Monig H, Arendt T, Meyer M, Kloehn S, Bewig B.

Klinik fur Allgemeine Innere Medizin, Christian-Albrechts-Universitat zu Kiel, Germany. hmoenig@1med.uni-kiel.de

OBJECTIVE: To determine whether cytokine release or activation of the hypothalamo-pituitary-adrenal (HPA) axis is predominantly involved in the development of the euthyroid sick syndrome (ESS). DESIGN: Prospective observational study. SETTING: Intensive care unit at a tertiary care medical center in Germany. PATIENTS: Nine patients with sepsis of different causes and eight patients with acute myocardial infarction. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Immediately on admission and on day 7 the following parameters were determined: total thyroxine (T4), free thyroxine (FT4), total triiodothyronine (T3), thyrotropin (TSH), interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), serum cortisol and plasma adrenocorticotropin (ACTH). On admission, concentrations of all thyroid hormones and TSH were significantly lower in septic patients compared to non-septic patients, whereas all cytokines except IL-2 were significantly elevated in the sepsis group. By contrast, there was no difference in serum cortisol and plasma ACTH levels between the two groups. On day 7, T4 and T3 were still lower in the septic group, whereas IL-1 beta, sIL-2R and IL-6 were still elevated. Again, no differences were found with regard to cortisol and ACTH levels. CONCLUSIONS: Euthyroid sick syndrome occurs very early during the course of septic diseases. Significantly decreased levels of total T4, FT4, T3 and TSH in septic patients suggest central suppression of TSH as well as inhibition of thyroid hormone release in ESS. The HPA axis is activated in septic patients and in non-septic patients and does not contribute to the development of ESS.

PMID: 10660848 [PubMed - indexed for MEDLINE]

1: Chest. 1991 Jan;99(1):169-75. Links

Endotoxemia in human septic shock.

Danner RL, Elin RJ, Hosseini JM, Wesley RA, Reilly JM, Parillo JE.

Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Md 20892.

To evaluate the incidence, pattern and clinical importance of endotoxemia in septic shock, frequent, serial endotoxin determinations were made prospectively in patients with shock. Detectable endotoxin occurred in 43 of 100 patients with septic shock, but in only one of ten patients with shock due to nonseptic causes. During septic shock, endotoxemia frequently occurred in the absence of Gram-negative bacteremia. Using a logistic regression model, multiple organ failure occurred 10.3 times more frequently and depression of left ventricular ejection fraction (less than or equal to 45 percent) 4.8 times more frequently in endotoxemic patients. In patients with positive blood cultures, endotoxemia was associated with a high mortality. We conclude that endotoxemia occurs frequently in septic shock and is associated with severe manifestations of this syndrome, including cardiac depression and multiple organ failure. This study suggests that endotoxin is an important mediator of septic shock and supports efforts to develop anti-endotoxin therapies for treating patients with this disease.

PMID: 1984950 [PubMed - indexed for MEDLINE]

Definition of antigen: autoantigen (au·to·an·ti·gen) (aw”to-an´tĭ-jen) an antigen that, despite being a normal tissue constituent, is the target of a humoral or cell-mediated immune response, as in autoimmune disease.

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1: Endocrinology. 2006 Jul;147(7):3260-75. Epub 2006 Apr 20.

Bacterial lipopolysaccharide stimulates the thyrotropin-dependent thyroglobulin gene expression at the transcriptional level by involving the transcription factors thyroid transcription factor-1 and paired box domain transcription factor 8.

Velez ML, Costamagna E, Kimura ET, Fozzatti L, Pellizas CG, Montesinos MM, Lucero AM, Coleoni AH, Santisteban P, Masini-Repiso AM.

Departamento de Bioquimica Clinica, Facultad de Ciencias Quimicas, Centro de Investigaciones en Bioquimica Clinica e Inmunologia, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Universidad Nacional de Cordoba, 5000 Cordoba, Argentina.

The bacterial lipopolysaccharide (LPS) is a biological activator that induces expression of multiple genes in several cell types. LPS has been proposed as an etiopathogenic agent in autoimmune diseases. However, whether LPS affects the expression of autoantigens has not been explored. Thyroglobulin (TG) is a key protein in thyroid hormonogenesis and one of the major thyroid autoantigens. This study aimed to analyze the action of LPS on TG gene expression in Fisher rat thyroid cell line FRTL-5 thyroid cells. We demonstrate that LPS increases the TSH-induced TG protein and mRNA level. Evidence that the effect of LPS is exerted at the transcriptional level was obtained by transfecting the minimal TG promoter. The C element of the TG promoter, which contains sequences for paired box domain transcription factor 8 (Pax8) and thyroid transcription factor (TTF)-1 binding, is essential for full TG promoter expression under TSH stimulation. The transcriptional activity of a construct containing five tandem repeats of the C site is increased by LPS, indicating a possible involvement of the C site in the LPS-induced TG gene transcription. We demonstrate that the TG promoter mutated at the Pax8 or TTF-1 binding element in the C site does not respond to LPS. In band shift assays, binding of Pax8 and TTF-1 to the C site is increased by LPS. The Pax8 and TTF-1 mRNA and protein levels are augmented by LPS. The half-lives of TG, Pax8, and TTF-1 are increased in endotoxin-treated cells. Our results reveal the ability of LPS to stimulate the expression of TG, a finding of potential pathophysiological implication.

LPS may contribute to the development of goiter

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Interleukin-1 production and action in thyroid tissue

Y Kawabe, K Eguchi, C Shimomura, M Mine, T Otsubo, Y Ueki, H Tezuka, H Nakao, A Kawakami and K Migita

First Department of Internal Medicine, Nagasaki University School of Medicine, Japan.

This study was undertaken to determine the effects of interleukin-1 (IL- 1) on human thyroid epithelial cells (thyrocytes) and whether thyrocytes produce IL-1. The supernatants of cultured peripheral blood monocytes stimulated with lipopolysaccharide (LPS) increased [3H]thymidine incorporation into thyrocytes from normal subjects and patients with Grave's disease. The IL-1 levels of cultured supernatants of monocytes were measured by a thymocyte costimulation assay and a solid phase sandwich immunoenzymometric assay. The supernatants of monocyte cultures stimulated with LPS contained significant amounts of IL-1 bioactivity and IL-1 alpha and IL-1 beta immunoactivity. Recombinant IL-1 beta (rIL-1 beta) also stimulated [3H]thymidine incorporation into thyrocytes from normal subjects and patients with Graves' disease, and it increased the proportion of thyrocytes in the S phase of the cell cycle. Furthermore, thyrocytes stimulated with rIL-1 beta for 24 h produced significant amounts of prostaglandin E2. Indomethacin inhibited completely the rIL-1 beta-stimulated prostaglandin E2 production and increased markedly [3H]thymidine incorporation. IL-1-like activity also was detected in the cultured supernatants of lipopolysaccharide (LPS)-stimulated thyrocytes from Graves' and normal thyroid glands, but the amount of IL-1-like activity secreted by thyrocytes was significantly less than that secreted by circulating monocytes. The kinetics of the release of IL-1-like activity by thyrocytes were similar to those of its production by circulating monocytes. Pretreatment of thyrocytes with interferon-gamma failed to enhance the release of IL-1-like activity. Moreover, IL-1 alpha or IL-1 beta immunoreactivity could not be detected in the supernatants of LPS-stimulated thyrocytes, despite the presence of IL-1- like bioactivity. No IL-1 alpha mRNA was detected in unstimulated thyrocytes or thyrocytes stimulated with LPS and phorbol myristate acid. These findings demonstrate that thyrocytes produce an IL-1-like substance(s), but not IL-1, when stimulated by LPS. We conclude that IL- 1 may regulate the proliferation of thyrocytes and that local production of IL-1 by infiltrating monocytes may contribute to the development of goiter in patients with autoimmune thyroid diseases.

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.

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1: J Endocrinol. 2005 Oct;187(1):17-24.Click here to read Links

Autoinduction of tumor necrosis factor-alpha in FRTL-5 rat thyroid cells.

* Mori K, * Yoshida K, * Komatsu A, * Tani J, * Nakagawa Y, * Hoshikawa S, * Ito S.

Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. kokimori@mail.tains.tohoku.ac.jp

Tumor necrosis factor-alpha (TNFalpha) may play a role in the development of autoimmune thyroiditis such as Hashimoto's thyroiditis. In the present study, we examined whether TNFalpha induced its own expression in FRTL-5 rat thyroid cells. Lipopolysaccharide (LPS) markedly increased TNFalpha mRNA levels in FRTL-5 cells as assessed by semiquantitative RT-PCR. In addition, LPS-stimulated cells released TNFalpha protein into the culture medium. Similarly, TNFalpha induced its own gene and protein expression in FRTL-5 cells as assessed by RT-PCR and metabolic labeling and immunoprecipitation of TNFalpha. The autoinduction of TNFalpha gene was also observed in TNFalpha-stimulated human thyroid epithelial cells. TNFalpha induction was specific to LPS and TNFalpha since interferon-alpha or amiodarone failed to increase TNFalpha mRNA levels in FRTL-5 cells. Human TNFalpha induced rat TNFalpha gene expression, indicating that type 1 TNF receptor (TNF-R) is involved in the autoinduction. TNFalpha did not increase either type 1 or type 2 TNF-R mRNA levels, suggesting that upregulation of TNF receptors is not involved in the autoinduction of TNFalpha. Although the biological significance of autoinduction of TNFalpha remains unclear, our results suggest that thyroid epithelial cells may participate in the development of autoimmune thyroiditis through production of TNFalpha. Furthermore, inhibition of TNFalpha production in the thyroid may represent a novel approach to mitigating inflammation in autoimmune thyroiditis.

PMID: 16214937 [PubMed - indexed for MEDLINE]