Kouki Mori

Viral infection activates both the innate and adaptive immunity and is implicated as a trigger of autoimmune diseases including Hashimoto's thyroiditis. This review summarizes our knowledge respecting the role of viral infection in the cause of Hashimoto's thyroiditis. Components of several viruses such as hepatitis C virus, human parvovirus B19, coxsackie virus and herpes virus are detected in the thyroid of Hashimoto's thyroiditis patients. Bystander activation of autoreactive T cells may be involved in triggering intrathyroidal inflammation. Signaling molecules associated with antiviral responses including Toll-like receptors may participate in Hashimoto's thyroiditis induction. However, studies have provided insufficient direct evidence for the viral hypothesis in Hashimoto's thyroiditis. Despite interesting circumstantial evidence, whether viral infection is responsible for Hashimoto's thyroiditis remains unclear. Studies addressing this issue are required to substantiate a contribution from viral infection to Hashimoto's thyroiditis and, consequently, the prospect for developing preventive modalities for Hashimoto's thyroiditis.

We explored the role of interleukin-6 (IL-6) in the development of autoimmune thyroiditis in nonobese diabetic (NOD) mice, an animal model of Hashimoto's thyroiditis, using anti-mouse IL-6 receptor antibody (MR16-1). Thyroiditis was induced by iodide ingestion or mouse thyroglobulin (Tg) immunization. Mice were injected intraperitoneally with saline, control rat IgG, or MR16-1 (2 or 8 mg). Iodide ingestion did not increase serum IL-6 levels and MR16-1 (2 mg) failed to prevent the development of thyroiditis. In contrast, Tg immunization induced a rapid and significant increase in serum IL-6 levels. While MR16-1 (2 mg) had no effect on Tg-induced thyroiditis, the severity, but not incidence, of thyroiditis was reduced in 8 mg MR16-1-treated mice compared with saline-injected mice. However, thyroiditis development in the 8 mg MR16-1-treated mice was indistinguishable from that in the control IgG-treated mice. MR16-1 (8 mg) did not affect serum anti-Tg antibody levels. These results suggest that IL-6 may play only a minor role in the development of autoimmune thyroiditis in NOD mice.

Tumor necrosis factor-α (TNFα) may play a role in the development of autoimmune thyroiditis such as Hashimoto’s thyroiditis. In the present study, we examined whether TNFα induced its own expression in FRTL-5 rat thyroid cells. Lipopolysaccharide (LPS) markedly increased TNFα mRNA levels in FRTL-5 cells as assessed by semiquantitative RT-PCR. In addition, LPS-stimulated cells released TNFα protein into the culture medium. Similarly, TNFα induced its own gene and protein expression in FRTL-5 cells as assessed by RT-PCR and metabolic labeling and immunoprecipitation of TNFα. The autoinduction of TNFα gene was also observed in TNFα-stimulated human thyroid epithelial cells. TNFα induction was specific to LPS and TNFα since interferon-α or amiodarone failed to increase TNFα mRNA levels in FRTL-5 cells. Human TNFα induced rat TNFα gene expression, indicating that type 1 TNF receptor (TNF-R) is involved in the autoinduction. TNFα did not increase either type 1 or type 2 TNF-R mRNA levels, suggesting that upregulation of TNF receptors is not involved in the autoinduction of TNFα. Although the biological significance of autoinduction of TNFα remains unclear, our results suggest that thyroid epithelial cells may participate in the development of autoimmune thyroiditis through production of TNFα. Furthermore, inhibition of TNFα production in the thyroid may represent a novel approach to mitigating inflammation in autoimmune thyroiditis.