TRAIL and DR5 Promote Thyroid Follicular Cell Apoptosis in Iodine Excess-Induced Experimental Autoimmune Thyroiditis in NOD Mice

Abstract

Death receptor-mediated apoptosis has been implicated in target organ destruction in patients with chronic autoimmune thyroiditis. Several apoptosis signaling pathways, such as Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), have been shown to be active in thyroid cells and may be involved in destructive thyroiditis. Thyroid toxicity of iodide excess has been demonstrated in animals fed with an iodide-rich diet, but its pathogenic role remains unclear. The effects of excessive iodine on TRAIL and its death receptor expression in thyroid were investigated. Experimental autoimmune thyroiditis (EAT) was induced by excessive iodine and thyroglobulin (Tg) in non-obese diabetic mice. The expression of TRAIL and its death receptor DR5 was detected by immunofluorescence staining. Following administration of excessive iodine alone, Tg, and excessive iodine combined with Tg, TRAIL-positive cells appear not only in follicular cells but also in lymphocytes infiltrated in the thyroid, whereas DR5-positive cells appear only in follicular cells. Large numbers of CD3-positive cells and a few CD22-positive cells were detected in thyroid. A great amount of follicular cells were labeled specifically by terminal deoxynucleotide transferase-mediated deoxynucleotide triphosphate nick-end labeling assay. Taken together, our results suggest that excessive iodine could induce TRAIL and DR5 abnormal expression in thyroid. TRAIL band with DR5 to promote follicular cells apoptosis thus mediate thyroid destruction in EAT.

The Role of Iodine and Selenium in Autoimmune Thyroiditis

“…A number of apoptosis signaling pathways, including Fas ligand and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), are thought to be implicated in destructive thyroiditis. It is thus probable that excessive iodine induces TRAIL abnormal expression in the thyroid, promotes follicular cells apoptosis, and mediates thyroid destruction [40].…”

Iodine Excess as an Environmental Risk Factor for Autoimmune Thyroid Disease

“…In thyroid, follicular cell injury, apoptosis and necrosis that precede lymphocytic infiltration in the thyroid are considered the initial events in, and prerequisites for, the development of iodine-induced autoimmune thyroiditis [85,86]. Activation of several death receptor-mediated signaling pathways, including Fas ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and B-cell lymphoma (Bcl)-2-associated X protein, is consistently observed in thyrocytes after iodine treatment [86].…”

“…Activation of several death receptor-mediated signaling pathways, including Fas ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and B-cell lymphoma (Bcl)-2-associated X protein, is consistently observed in thyrocytes after iodine treatment [86]. …”

Hashimotos Thyroiditis: From Genes to the Disease

“…Thirdly, iodine toxicity to thyrocytes has been reported, since highly reactive oxygen species may bind to membrane lipids and proteins, causing thyrocyte damage and release of autoantigens [ 112 ]. Fourthly, iodine excess has been shown to promote follicular cell apoptosis by inducing an abnormal expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor (DR)-5 in thyroid [ 116 ]. Fifthly, in vitro evidence also suggests an enhancing influence of iodine on the cells of the immune system, including augmented maturation of dendritic cells, increased number of T cells and stimulated B-cell immunoglobulin production [ 112 ].…”