Expression of TPO and ThOXs in human thyrocytes is downregulated by IL-1alpha/IFN-gamma, an effect partially mediated by nitric oxide.
Morphological and functional alterations in Hashimoto's thyroiditis (HT) are predominantly mediated by Th1 cytokines through apoptotic cell death. This ultimate step could be preceded by functional injuries in thyroid hormone synthesis. The action of two Th1 cytokines (IL-1alpha/IFN-gamma) on thyroperoxidase (TPO) and thyroid oxidase (ThOXs) expression was tested in human thyrocytes isolated from normal tissues, Graves' disease (GD) tissues, and autonomous toxic nodules. There was no evidence of cell death. Nitric oxide (NO) release was induced by cytokines but was absent when NG-nitro-L-arginine methyl ester (L-NAME) was coincubated. When thyrotropin (TSH)-incubated normal and GD thyrocytes were treated with IL-1alpha/IFN-gamma, TPO and ThOXs protein and mRNA expression dropped, a decrease partially prevented by L-NAME, suggesting that NO acts as a mediator of Th1 effects. In thyrocytes from autonomous toxic nodules, the high level of TPO and ThOXs protein expression was not influenced by TSH or by cytokines, a finding partially reproduced when normal thyrocytes were treated with increasing concentrations of TSH. In conclusion, incubation of normal or GD thyrocytes with Th1 cytokines induces a significant reduction in TSH-increased expression of both TPO and ThOXs, an effect partially mediated by NO. The thyroid cell function can therefore be severely affected in HT, even when cells remain viable. In autonomous toxic nodules, cells become partially insensitive to exogenous Th1 cytokines.
Gérard
Anne-Catherine
AC
Unité de Morphologie Expérimentale (MOEX), Université catholique de Louvain, UCL-5251, 52 Av. E. Mounier, B-1200, Brussels, Belgium.
Boucquey
Marie
M
van den Hove
Marie-France
MF
Colin
Ides M
IM
D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D000074623:Dual Oxidases; D005420:Flavoproteins / Q000378:metabolism*; D006111:Graves Disease / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D007375:Interleukin-1 / Q000008:administration & dosage*; D007453:Iodide Peroxidase / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism*
D005420:Flavoproteins; D007375:Interleukin-1; D009569:Nitric Oxide; D007371:Interferon-gamma; D000074623:Dual Oxidases; D007453:Iodide Peroxidase; D019255:NADPH Oxidases; C431513:DUOX1 protein, human; C431515:DUOX2 protein, human