Overexpression of IL-4 in the thyroid of transgenic mice upregulates the expression of Duox1 and the anion transporter pendrin.

Overexpression of IL-4 in the thyroid of transgenic mice upregulates the expression of Duox1 and the anion transporter pendrin.

Thyroid. 2016 Sep 6;

Authors: Eskalli Z, Achouri Y, Hahn S, Many MC, Craps J, Refetoff S, Liao XH, Dumont JE, Van Sande J, Corvilain B, Miot F, De Deken X

Abstract
BACKGROUND: The dual oxidases (Duox) are thyroid-functional markers involved in H2O2-generation, which is essential for thyroid hormone synthesis. During inflammation, cytokines upregulate DUOX gene expression in the airway and the intestine, suggesting a role for these proteins in innate immunity. We previously demonstrated that interleukin-4 (IL-4) upregulates DUOX gene expression in thyrocytes. Although the role of IL-4 in autoimmune thyroid diseases (AITD) has been studied extensively, the effects of IL-4 on thyroid physiology remain largely unknown. Therefore, we generated a new animal model to study the impact of IL-4 on thyroid function.
METHODS: Transgenic (Thyr-IL-4) mice with thyroid-targeted expression of murine IL-4 were generated. Transgene expression was verified at the mRNA and protein level in thyroid tissues and primary cultures. The phenotype of the Thyr-IL-4 animals was characterized by measuring serum T4 and TSH levels and performing thyroid morphometric analysis, immunohistochemistry, whole transcriptome sequencing, quantitative RT-PCR, and ex vivo thyroid function assays.
RESULTS: Thyrocytes from two Thyr-IL-4 mouse lines (#30 and #52) expressed IL-4, which was secreted into the extracellular space. Although ten month-old transgenic animals had T4 and TSH serum levels in the normal range, they had altered thyroid follicular structure with enlarged follicles composed of elongated thyrocytes containing numerous endocytic vesicles. These follicles were positive for T4 staining the colloid indicating their capacity to produce thyroid hormones. RNA profiling of Thyr-IL-4 thyroid samples revealed modulation of multiple genes involved in inflammation, while no major leukocyte infiltration could be detected. Upregulated expression of Duox1, Duoxa1, and the pendrin anion exchanger gene (Slc26a4) was detected. In contrast, the iodide symporter gene Slc5a5 was markedly downregulated resulting in impaired iodide uptake and reduced thyroid hormone levels in transgenic thyroid tissue. H2O2 production was increased in Thyr-IL-4 thyroid tissue compared to wild type animals, but no significant oxidative stress could be detected.
CONCLUSIONS: This is the first study to show that ectopic expression of IL-4 in thyroid tissue upregulates Duox1/Duoxa1 and Slc26a4 expression in the thyroid. The present data demonstrate that IL-4 could affect thyroid morphology and function, mainly by downregulating Slc5a5 expression, while maintaining a normal euthyroid phenotype.

PMID: 27599561 [PubMed - as supplied by publisher]

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