Complete inhibition of rhTSH-, Graves' disease IgG-, and M22-induced cAMP production in differentiated orbital fibroblasts by a low-molecular-weight TSHR antagonist.
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| Abstract |
The TSH receptor (TSHR) on orbital fibroblasts (OF) is a proposed target of the autoimmune attack in Graves' ophthalmopathy. In the present study, we tested whether the novel low-molecular-weight (LMW) TSHR antagonist Org-274179-0 inhibits cAMP production induced by rhTSH, Graves' disease IgG (GD-IgG), or M22 (a potent human monoclonal TSHR stimulating antibody) in cultured and differentiated OF from Graves' ophthalmopathy patients. cAMP production significantly increased after incubation either with 10 mU/ml rhTSH (3-fold; P ≤ 0.05), 1 mg/ml GD-IgG (2-fold; P ≤ 0.05), or 500 ng/ml M22 (5-fold; P ≤ 0.05). Incubation with the LMW TSHR antagonist dose dependently inhibited rhTSH, GD-IgG as well as the M22-induced cAMP production at nanomolar concentrations; complete blockade was affected at 10(-6) M. Our results suggest that GD-IgG- and M22-induced cAMP production in differentiated OF is exclusively mediated via the TSHR because it can be completely blocked by the LMW TSHR antagonist, Org 274179-0.
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| Authors | Clementine J J van Zeijl, Chris J van Koppen, Olga V Surovtseva, Marcel E de Gooyer, Ralf Plate, Paolo Conti, Willem-Jan Karstens, Marco Timmers, Peerooz Saeed, Wilmar M Wiersinga, André M M Miltenburg, Eric Fliers, Anita Boelen |
| Journal | The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 97 Issue 5 Pg. E781-5 (May 2012) ISSN: 1945-7197 [Electronic] United States |
| PMID | 22419705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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