Hong Chen1, Tünde Mester, Nupur Raychaudhuri, Courtney Y Kauh, Shivani Gupta, Terry J Smith, Raymond S Douglas. 1. Departments of Ophthalmology and Visual Sciences (H.C., R.S.D., T.M., N.R., C.Y.K., S.G., T.J.S.) and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor, Michigan 48105; Ann Arbor Veterans Administration Medical Center (R.S.D.), Ann Arbor, Michigan 48105; and Department of Ophthalmology of Union Hospital (H.C.), Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, People's Republic of China.
Abstract
CONTEXT: Thyroid-associated ophthalmopathy (TAO) is the component of Graves' disease characterized by orbital inflammation and connective tissue remodeling. The IGF-1 receptor (IGF-1R) and TSH receptor (TSHR) form a physical and functional complex in orbital fibroblasts. A subset of these fibroblasts is derived from infiltrating CD34(+) fibrocytes. Teprotumumab (RV 001, R1507) is a human monoclonal anti-IGF-1R blocking antibody currently undergoing a phase 2 clinical trial in patients with active TAO. OBJECTIVE: To determine whether teprotumumab inhibits the induction by TSH of IL-6 and IL-8 in fibrocytes. DESIGN: Fibrocytes were treated without or with teprotumumab in combination with IGF-1 or TSH. MAIN OUTCOME MEASURES: IL-6 and IL-8 mRNA expression and protein production were analyzed by real-time PCR and Luminex, respectively. Phosphorylated Akt (S473) levels were analyzed by Western blot. TSHR and IGF-1R display was assessed by flow cytometry. RESULTS: Fibrocyte display of IGF-1R and TSHR was reduced with teprotumumab, as were IGF-1- and TSH-dependent phosphorylated Akt levels. TSH induction of IL-6 and IL-8 mRNA and protein was also reduced by the monoclonal antibody. CONCLUSIONS: Teprotumumab attenuates the actions of both IGF-1 and TSH in fibrocytes. Specifically, it blocks the induction of proinflammatory cytokines by TSH. These results provide, at least in part, the molecular rationale for interrogating the therapeutic efficacy of this antibody in TAO.
CONTEXT: Thyroid-associated ophthalmopathy (TAO) is the component of Graves' disease characterized by orbital inflammation and connective tissue remodeling. The IGF-1 receptor (IGF-1R) and TSH receptor (TSHR) form a physical and functional complex in orbital fibroblasts. A subset of these fibroblasts is derived from infiltrating CD34(+) fibrocytes. Teprotumumab (RV 001, R1507) is a human monoclonal anti-IGF-1R blocking antibody currently undergoing a phase 2 clinical trial in patients with active TAO. OBJECTIVE: To determine whether teprotumumab inhibits the induction by TSH of IL-6 and IL-8 in fibrocytes. DESIGN: Fibrocytes were treated without or with teprotumumab in combination with IGF-1 or TSH. MAIN OUTCOME MEASURES: IL-6 and IL-8 mRNA expression and protein production were analyzed by real-time PCR and Luminex, respectively. Phosphorylated Akt (S473) levels were analyzed by Western blot. TSHR and IGF-1R display was assessed by flow cytometry. RESULTS: Fibrocyte display of IGF-1R and TSHR was reduced with teprotumumab, as were IGF-1- and TSH-dependent phosphorylated Akt levels. TSH induction of IL-6 and IL-8 mRNA and protein was also reduced by the monoclonal antibody. CONCLUSIONS:Teprotumumab attenuates the actions of both IGF-1 and TSH in fibrocytes. Specifically, it blocks the induction of proinflammatory cytokines by TSH. These results provide, at least in part, the molecular rationale for interrogating the therapeutic efficacy of this antibody in TAO.
Authors: Ricardo Núñez Miguel; Jane Sanders; Paul Sanders; Stuart Young; Jill Clark; Katarzyna Kabelis; Jane Wilmot; Michele Evans; Emma Roberts; Xiaoling Hu; Jadwiga Furmaniak; Bernard Rees Smith Journal: J Mol Endocrinol Date: 2012-08-30 Impact factor: 5.098
Authors: Aimee J Varewijck; Anita Boelen; Steven W J Lamberts; Eric Fliers; Leo J Hofland; Wilmar M Wiersinga; Joseph A M J L Janssen Journal: J Clin Endocrinol Metab Date: 2013-01-07 Impact factor: 5.958