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-γ, tumor necrosis factor-α, interleukin-1β 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 I and ICAM-1 mRNA levels in FRTL-5 cells; furthermore, TSH/cAMP inhibit cytokines (interferon-γ, tumor necrosis factor-α)-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-γ and tumor necrosis factor-α 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.
Highlights
The pathogenesis of human and animal autoimmune thyroid diseases is still obscure
These observations led to the hypothesis that hormonal suppression of major histocompatibility complex (MHC) class I gene expression maintains low class I levels, thereby preserving self tolerance in the face of hormone action to increase the expression of thyroid specific thyroglobulin, thyroperoxidase or ubiquitous genes during thyroid stimulating hormone (TSH) induced growth and function (Kohn et al, 1995)
We have recently shown that FRTL-5 cells and human thyroid follicular cells from Graves’ disease and Hashimoto disease express ICAM1 which is detectable by usual Northern blot analysis and immunocytochemistry (Shong et al, 1994b)
Summary
Several immunological and target cell factors are discussed as initiative abnormalities in the development of autoimmune thyroid disease. Our previous studies of the regulation of thyrotropin receptor and MHC class I gene in the rat FRTL-5 thyroid cell revealed that TSH/cAMP actively suppresses the expression of these molecules at the transcriptional level (Ikuyama et al, 1992; Saji et al, 1992a-c; Giuliani et al, 1995). Most of hormones or growth factors associated with maximal FRTL-5 thyroid cell growth suppressed MHC class I gene expression (Saji et al, 1992a-c; Giuliani et al, 1995). These observations led to the hypothesis that hormonal suppression of MHC class I gene expression maintains low class I levels, thereby preserving self tolerance in the face of hormone action to increase the expression of thyroid specific thyroglobulin, thyroperoxidase or ubiquitous genes during TSH induced growth and function (Kohn et al, 1995)
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