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* Division of Molecular Medicine and
Department of Medicine, Division of Endocrinology, Harbor-UCLA Medical Center, Torrance, CA 90502;
Jules Stein Eye Institute, Los Angeles, CA 90095;
The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095; and
¶ Veterans Administration Medical Center, Long Beach, CA 90822
Thyroid-stimulating hormone receptor (TSHR) plays a central role in regulating thyroid function and is targeted by IgGs in Graves’ disease (GD-IgG). Whether TSHR is involved in the pathogenesis of thyroid-associated ophthalmopathy (TAO), the orbital manifestation of GD, remains uncertain. TSHR signaling overlaps with that of insulin-like grow factor 1 receptor (IGF-1R). GD-IgG can activate fibroblasts derived from donors with GD to synthesize T cell chemoattractants and hyaluronan, actions mediated through IGF-1R. In this study, we compare levels of IGF-1R and TSHR on the surfaces of TAO and control orbital fibroblasts and thyrocytes and explore the physical and functional relationship between the two receptors. TSHR levels are 11-fold higher on thyrocytes than on TAO or control fibroblasts. In contrast, IGF-1R levels are 3-fold higher on TAO vs control fibroblasts. In pull-down studies using fibroblasts, thyrocytes, and thyroid tissue, Abs directed specifically against either IGF-1Rβ or TSHR bring both proteins out of solution. Moreover, IGF-1Rβ and TSHR colocalize to the perinuclear and cytoplasmic compartments in fibroblasts and thyrocytes by confocal microscopy. Examination of orbital tissue from patients with TAO reveals similar colocalization to cell membranes. Treatment of primary thyrocytes with recombinant human TSH results in rapid ERK phosphorylation which can be blocked by an IGF-1R-blocking mAb. Our findings suggest that IGF-1R might mediate some TSH-provoked signaling. Furthermore, they indicate that TSHR levels on orbital fibroblasts are considerably lower than those on thyrocytes and that this receptor associates with IGF-1R in situ and together may comprise a functional complex in thyroid and orbital tissue.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants EY011708, EY008976, EY016339, DK063121, RR017304, and HD39293 from the National Institutes of Health, by a Merit Review award from the Research Service of the Department of Veterans Affairs, and by the Bell Charitable Trust.
2 Address correspondence and reprint requests to Dr. Terry J. Smith, Division of Molecular Medicine, Harbor-UCLA Medical Center, Building C-2, 1124 West Carson Street, Torrance, CA 90502. E-mail address: tjsmith{at}ucla.edu
3 Abbreviations used in this paper: IGF-1R, insulin-like growth factor 1 receptor; TSHR, thyroid-stimulating hormone; GD, Graves’ disease; TAO, thyroid-associated ophthalamopathy; rhTSH, recombinant human TSH; siRNA, short interfering RNA; MFI, mean fluorescence intensity; ABC, Ab-binding capacity.
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