Thyroid hydrogen peroxide production is enhanced by the Th2 cytokines, IL-4 and IL-13, through increased expression of the dual oxidase 2 and its maturation factor DUOXA2

Abstract

The dual oxidases (DUOX) 1 and 2 constitute the major components of the thyroid H(2)O(2)-generating system required for thyroid hormone synthesis. With their maturation factor, DUOXA1 or DUOXA2, they share the same bidirectional promoter allowing coexpression of DUOX/DUOXA in the same tissue. However, the molecular mechanisms regulating their transcription in the human thyroid gland are not well characterized yet. Inflammatory molecules associated with autoimmune thyroid diseases have been shown to repress the thyroid function by down-regulating the expression of the major thyroid differentiation markers. These findings led us to investigate the effects of the main cytokines involved in Hashimoto thyroiditis (IFN-γ) and Graves' diseases (IL-4/IL-13) on the transcriptional regulation of DUOX and their corresponding DUOXA genes in thyroid cells. Human thyrocytes exposed to the Th2 cytokines IL-4 and IL-13 showed up-regulation of DUOX2 and DUOXA2 genes but not DUOX1/DUOXA1. The DUOX2/DUOXA2 induction was rapid and associated with a significant increase of calcium-stimulated extracellular H(2)O(2) generation. IFN-γ treatment inhibited DUOX gene expression and repressed the Th2 cytokine-dependent DUOX2/DUOXA2 expression. In another DUOX-expressing model, the human intestinal Caco-2 cell line, expression of DUOX2 and DUOXA2 mRNA was also positively modulated by IL-4 and IL-13. Analysis of the IL-4 signaling pathway revealed that the JAK1-STAT6 cascade activated by the IL-4 type 2 receptor is required for DUOX2/DUOXA2 induction. The present data open new perspectives for a better understanding of the pathophysiology of thyroid autoimmune diseases considering DUOX2-mediated oxidative damages.