The presence of adenosine A2a receptor in thyrocytes and its involvement in Graves' IgG-induced VEGF expression.
Goitrogenesis in Graves' disease (GD) has been attributed to anti-TSH receptor antibody stimulation. Recently, a role for adenosine A2a receptor (A2aR) in goiter formation was reported in the thyroglobulin-A2aR transgenic mice. However, it is unclear whether A2aR is expressed in the thyroid and whether it is associated with the pathogenesis of goiter in GD. Here, we confirmed the expression of A2aR in FRTL-5 cells, primary normal human thyrocytes (both sexes were used without regard to sex), and thyroid tissue (both sexes were used without regard to sex) by PCR, Western blotting, immunohistochemistry, and immunofluorescence. After treatments with A2aR-specific agonist 2-p-(2-Carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine or GD IgG, the mRNA and protein levels of vascular endothelial growth factor (VEGF), a growth factor related to goitrogenesis, were evaluated along with upstream signaling pathways. A2aR activation and GD IgG promoted the expression of VEGF in thyrocytes, which was accompanied by the activation of cAMP/protein kinase A/phosphorylated-cAMP-response element-binding protein, peroxisome proliferator-activated receptor γ coactivator-1α, and hypoxia-inducible factor-1α. The changes induced by GD IgG were partially abrogated by A2aR small interfering RNA and an A2aR antagonist. These results were supported by data on the goiter samples from the thyrotropin receptor adenovirus-induced GD mouse model (female). These data demonstrate that GD IgG could up-regulate the VEGF expression through A2aR, indicating a potential mechanism for goitrogenesis in GD.
Department of Endocrinology, Shandong Provincial Hospital, 324 Jing 5 Road, Jinan, Shandong Province 250021, China. gaoling1@medmail.com.cn.
Lin
L
Zhang
Jin
J
Xu
Nannan
N
Sun
Hu
H
Cai
Meng
M
Ren
Jie
J
Zhang
Chunxiao
C
Yu
Zhe
Z
Wang
Ling
L
Gao
Jiajun
J
Zhao
D000818:Animals; D005260:Female; D006111:Graves Disease / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020033:Protein Isoforms; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013961:Thyroid Gland / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D007074:Immunoglobulin G; D020033:Protein Isoforms; D043705:Receptor, Adenosine A2A; D042461:Vascular Endothelial Growth Factor A