Reduced expression of interleukin 6 in undifferentiated thyroid carcinoma: in vitro and in vivo studies

Cytokines appear to play an important role in the development and progression of epithelial tumors. Cultured normal human thyroid follicular cells constitutively release high levels of interleukin-6 (IL-6) and IL-8, together with low to moderate levels of transforming growth factor-alpha (TGF-alpha) and TGF-beta. IL-6 appears to play multiple functions in thyroid physiology and disease. Because certain data indicate an inverse relationship between IL-6 production and epithelial tumor aggressiveness, we used both tissue culture methods and histochemical techniques to search for possible alterations of cytokine expression in thyroid carcinomas. As compared to cultures from normal tissue and well-differentiated carcinoma, production of IL-6 was strongly down-regulated in cultures derived from undifferentiated carcinoma. In contrast, levels of IL-8, TGF-alpha, and TGF-beta produced by neoplastic TFC were similar to those produced by normal cells. Actually, production of TGF-alpha was slightly enhanced in cultures from well-differentiated carcinoma. Immunoassay results were confirmed by reverse transcriptase-PCR analysis. Immunohistochemistry of human thyroid carcinomas (n = 99) and normal thyroid tissue (n = 85) showed that immunoreactive IL-6 was strongly diminished in undifferentiated forms (n = 34) and slightly reduced in well-differentiated carcinoma (n = 65). In agreement with the in vitro results, TGF-alpha expression was significantly increased in neoplastic thyrocytes, as compared to their normal counterpart. The results indicate that, as in the mammary and salivary glands, down-regulation of IL-6 expression may represent a marker of undifferentiated thyroid carcinoma.