Increased expression of tumor necrosis factor-α and decreased expression of thyroglobulin and thyroid peroxidase mRNA levels in the thyroids of iodide-treated BB/Wor rats

Several lines of evidence suggest that tumor necrosis factor-alpha (TNF alpha) may contribute to the pathogenesis of autoimmune thyroid disease. It is not known, however, whether increased thyroidal TNF alpha levels are associated with changes in thyroid function. The purpose of the present study was to utilize in situ hybridization histochemistry and immunohistochemistry to determine if the expression of TNF-alpha in the thyroid is associated with a decrease in thyroglobulin (Tg) and thyroid peroxidase (TPO) mRNA levels. Lymphocytic thyroiditis was induced in BB/Wor rats by iodide administration, and thyroidal Tg and TPO mRNA levels were assessed by Northern blot analysis and in situ hybridization, and TNF alpha expression by Northern blot analysis and immunohistochemistry. Thyroids were obtained before and 1 and 2 months after iodide administration. Hematoxylin and eosin staining revealed that there was a progressive increase in mononuclear cells in the thyroids of BB/Wor rats ingesting iodide for 1 and 2 months. Northern blot analysis revealed that during the same time course there was a progressive increase in TNF alpha mRNA levels and a progressive decrease in Tg and TPO mRNA levels in the thyroids. In situ hybridization histochemistry was performed to determine if the decrease in Tg and TPO mRNA levels was associated with thyroid follicular cells in contact with infiltrating mononuclear cells. In rats treated with iodide for 1 month, there was a modest decrease in Tg and TPO mRNA levels in follicular cells in contact with infiltrating mononuclear cells. After 2 months of iodide treatment there was clearly a localized decrease in Tg and TPO mRNA levels in follicular cells in contact with infiltrating mononuclear cells. Immunohistochemical analysis did not detect TNF alpha in the thyroids from control rats or from rats treated with iodide for 1 month. In contrast, after 2 months of treatment, TNF alpha was easily detected in infiltrating mononuclear cells and in some thyroid follicular cells. Together, these results suggest that the suppression of Tg and TPO mRNA levels was associated with the expression of TNF alpha and thus are in agreement with in vitro studies demonstrating that TNF alpha inhibits thyroid cell function.