ABSTRACT
Our previous works have shown that human thyroid follicular cells from Graves' disease and FRTL-5 rat thyroid cells express the intercellular adhesion molecule-1 (ICAM-1) molecule and its expression is upregulated by several cytokines, interferon-gamma, tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6. We used FRTL-5 cells which show hormonal dependence of growth and function for the study of hormonal regulation of ICAM-1 gene, We studied ICAM-1 mRNA expression and promoter regulation after cloning of rat ICAM-1 promoter. We found very interesting findings that thyroid stimulating hormone (TSH) and forskolin downregulates steady state MHC class land ICAM-1 mRNA levels in FRTL-5 cells; furthermore, TSH/cAMP inhibit cytokines (interferon-gamma,tumor necrosis factor-alpha)-mediated maximal ICAM-1 mRNA expression, In addition, hydrocortisone and insulin differentially regulate the ICAM-1 mRNA levels; hydrocortisone markedly suppresses the mRNA level but insulin partially recovers hydrocortisone mediated ICAM-1 suppression, The interferon-gamma and tumor necrosis factor-alpha increases full ICAM-1 promoter (pCAM-1822) activity and this cytokine mediated increase of the promoter activity is also inhibited by TSH and forskolin, Thus TSH/cAMP pathways play roles as a antagonistic action for maximal expression of ICAM-1 gene by these cytokines. We propose this TSH action is one of physiologic mechanisms to preserve self tolerance in face of abnormal cytokine challenges in systemic inflammatory condition or acute phase response.
Subject(s)
Animals , Humans , Rats , Clone Cells , Cloning, Organism , Colforsin , Cytokines , Gene Expression , Graves Disease , Hydrocortisone , Insulin , Intercellular Adhesion Molecule-1 , Interferon-gamma , Interleukin-1beta , Interleukin-6 , Necrosis , RNA, Messenger , Self Tolerance , Thyroid Gland , Thyrotropin , Tumor Necrosis Factor-alphaABSTRACT
Background: TSH binding inhibiting imunoglobulins(TBII) are autoimmune antibody causing autoimmune thyroid diseases such as Graves disease or Hashimoto's thyroiditis, while intercellular adhesion molecule-1(ICAM-1) is known as a substance expressed at the site of autoimmune reaction in relation with lymphocyte infiltration. The serum TBII activity is used as an index of the disease course and prognosis of Graves disease treated with antithyroid drugs, propylthiouracil or methimazole. The aim of this study is to understand the change of serum ICAM-1 level according to the change of the degree of autoimmunity and clinical course of Graves disease. Methods: In order to study the change of soluble ICAM-1 and relationship to the immune mechanism of Graves' disease, we measured serum levels of TBII and ICAM-1 in patients(n 35) with Graves disease before and after treatment with antithyroid drugs and in relapsed patients using a highly sensitive ELISA method. Results: The serum levels of TBII and ICAM-1 were markedly elevated in patients with Graves disease before treatment than normal controls and there were good correlation between TBII and ICAM-1 level. In patients with normalized TBII levels after 22 months antithyroid drug treatment, the ICAM-1 levels became normal but in the patients with high serum TBII level showed high serum level of ICAM-1 even with clinical remission with same treatment. The serum levels of TBII and ICAM-1 in relapsed patients were elevated as those of patients before treatment. Conclusion: With the above results, we can conclude that not only the TBII level but seru ICAM-1 level also reflect the degree of autoimmune activity of Graves disease and may be used as an index of the disease course and prognosis of Graves disease treated with antithyroid drugs.