Abstract
BackgroundBID functions as a bridge molecule between death-receptor and mitochondrial related apoptotic pathways to amplify apoptotic signaling. Our previous studies have demonstrated a substantial increase in BID expression in primary normal thyroid epithelia cells treated with inflammatory cytokines, including the combination of IFNγ and IL-1β or IFNγ and TNFα. The aim of this study was to determine whether an increase in BID expression in thyroid can induce autoimmune thyroiditis.MethodsA transgenic mouse line that expresses human BID in thyroid cells was established by fusing a mouse thyroglobulin (Tg) promoter upstream of human BID (Tg-BID). We tested whether the increased expression of pro-apoptotic BID in thyroid would induce autoimmune thyroiditis, both in the presence and absence of 0.3% iodine water.ResultsOur data show that Tg-BID mice in a CBA/J (H-2 k) background do not spontaneously develop autoimmune thyroiditis for over a year. However, upon ingestion of iodine in the drinking water, autoimmune thyroiditis does develop in Tg-BID transgenic mice, as shown by a significant increase in anti-Tg antibody and mononuclear cell infiltration in the thyroid glands in 30% of mice tested. Serum T4 levels, however, were similar between iodine-treated Tg-BID transgenic mice and the wild type mice.ConclusionsOur data demonstrate that increased thyroid expression of BID facilitates the development of autoimmune thyroiditis induced by iodine uptake. However, the overexpression of BID itself is not sufficient to initiate thyroiditis in CBA/J (H-2 k) mice.
Highlights
BH3 interacting-domain death agonist (BID) functions as a bridge molecule between death-receptor and mitochondrial related apoptotic pathways to amplify apoptotic signaling
Despite the increase of serum anti-Tg antibody and mononuclear cell infiltration, serum T4 levels were similar between iodine-treated Tg-BID transgenic CBA/J (H-2 k) mice and wild-type CBA/J (H-2 k) mice. These findings suggest that the thyroid function of the Tg-BID transgenic mice appears within the normal range after receiving 8-week iodine in the drinking water, even though iodine uptake does result in a certain degree of autoimmune responses such as autoantibody production and mononuclear cell infiltration in Tg-BID transgenic mice
To test whether the genetic changes in BID play a role in the development of autoimmune thyroiditis, we successfully developed a transgenic mouse line in which BID is over-expressed in the thyroid
Summary
BID functions as a bridge molecule between death-receptor and mitochondrial related apoptotic pathways to amplify apoptotic signaling. Our previous studies have demonstrated a substantial increase in BID expression in primary normal thyroid epithelia cells treated with inflammatory cytokines, including the combination of IFNγ and IL-1β or IFNγ and TNFα. Our previous studies showed that the expression of BID in primary normal thyroid cells was significantly increased by inflammatory cytokines in vitro [3]. The pretreatment of those inflammatory cytokines can sensitize thyroid epithelia cells to death-receptor mediated apoptosis [2,3]. This finding suggests a potential role for BID in the pathogenesis of autoimmune thyroiditis. To test this hypothesis we first established a transgenic mouse line that expresses human BID in the thyroid, and tested whether the overexpression of BID alone is sufficient for the development of autoimmune thyroiditis
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