ANALYSIS OF CYTOKINE GENE-EXPRESSION IN GRAVES-DISEASE AND MULTINODULAR GOITER

Cytokines have a central role in the generation of an autoimmune respo nse and can directly affect the target organ. In Graves' disease, both the infiltrating mononuclear cells and the thyroid follicular cells p roduce certain cytokines, but the relative contribution of each is unc lear, and there are conflicting data on the exact profile of cytokines expressed within the thyroid. To clarify these issues, we used the me thod of reverse transcription-polymerase chain reaction amplification to analyze cytokine gene expression by intrathyroidal lymphocytes (ITL ) and purified thyroid follicular cells (TFC) from six patients with G raves' disease. All ITL samples were positive for interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-8, IL-10, and tumor necrosis factor- alpha (TNF alpha) messenger ribonucleic acids (mRNAs). Four samples we re positive for IL-2 mRNA, and of these, three were also positive for interferon-gamma (IFN gamma). All TFC samples contained IL-6 and IL-8 mRNAs, even after depletion of CD3-positive T-cells. One TFC sample wa s additionally positive for IL-10 and TNF alpha mRNAs, and in the case of IL-10, this signal was not eliminated by CD3-positive T-cell deple tion. IL-4 was not detected in any sample of ITL, TFC, or whole tissue . Semiquantitwo were also positive for IL-6, and 1 was positive for IL -8 mRNA. One multinodular goiter sample was positive for IL-8 mRNA alo ne, but IL-2, IL-4, IL-10, and TNF alpha mRNAs were not detected. Thes e results suggest that although the TFC themselves may express certain cytokines, the ITL population represents the most important source of cytokine production in Graves' thyroid glands. The presence of IL-2, IFN gamma, and TNF alpha and the absence of IL-4 mRNA in samples of IT L indicate a pattern of cytokine production that most closely resemble s that of the T(H)1 helper T-cell subset. Given the etiological role o f thyroid-stimulating antibodies in Graves' disease, the production of which is likely to depend upon T(H)2 helper T-cell function, it is pe rhaps surprising that the T(H)1 subset appears to predominate. It is p ossible that IL-10 is important in stimulating intrathyroidal autoanti body production, and this cytokine may also play a role in inhibiting cell-mediated thyroid injury in Graves' disease.