Complete inhibition of rhTSH-, Graves' disease IgG-, and M22-induced cAMP production in differentiated orbital fibroblasts by a low-molecular-weight TSHR antagonist

J Clin Endocrinol Metab. 2012 May;97(5):E781-5. doi: 10.1210/jc.2011-2931. Epub 2012 Mar 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / pharmacology*
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • CHO Cells
  • Cricetinae
  • Cyclic AMP / biosynthesis*
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Graves Disease / immunology*
  • Humans
  • Immunoglobulin G / pharmacology*
  • Orbit / cytology
  • Receptors, Thyrotropin / antagonists & inhibitors*
  • Thyrotropin / pharmacology*


  • Aminoquinolines
  • Antibodies, Monoclonal
  • Immunoglobulin G
  • N-(1-acetyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-3-(3-trifluoromethyl-phenyl)propionamide
  • Receptors, Thyrotropin
  • Thyrotropin
  • Cyclic AMP