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This version published online on January 12, 2006
Endocrinology, doi:10.1210/en.2005-1375
A more recent version of this article appeared on April 1, 2006
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Submitted on October 31, 2005
Accepted on December 19, 2005

IgG from patients with Graves' disease induces IL-16 and RANTES expression in cultured human thyrocytes: A putative mechanism for T cell infiltration of the thyroid in autoimmune disease

Andrew G. Gianoukakis, Raymond S. Douglas, Chris S. King, William W. Cruikshank, and Terry J. Smith*

Divisions of Molecular Medicine and Endocrinology and Metabolism (AGG, RSD, CSK, TJS), Harbor-UCLA Medical Center, Torrance, CA 90502, Jules Stein Eye Institute (RSD, TJS) and the David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095 USA and the Pulmonary Center (WWC), Boston University School of Medicine, Boston, MA 02118

* To whom correspondence should be addressed. E-mail: tjsmith{at}ucla.edu.

Mechanisms underlying lymphocyte infiltration of the thyroid gland and orbit in Graves' disease (GD) are poorly understood. The insulin growth factor-1 receptor (IGF-1R) is a newly recognized self-antigen that, when activated in GD fibroblasts by IGF-1 or GD-IgGs, provokes the expression of IL-16 and RANTES dependent T lymphocyte chemoattraction and hyaluronan synthesis. IL-16 is a CD4+-specific ligand and RANTES is a C-C chemokine. Here we report that IGF-1 and GD-IgG could induce IL-16 and RANTES in cultured human thyrocytes in a time-dependent manner. Importantly, human TSH failed to induce either chemoattractant. This induction could be attenuated by dexamethasone and rapamycin, a specific inhibitor of the FRAP/mTOR/p70s6k pathway, prevented GD-IgG-provoked IL-16 synthesis. IH7, a mAb directed at IGF-1R also blocked the induction of chemoattraction as well as RANTES mRNA synthesis. These thyrocytes display high levels of IGF-1R and TSHR. Our findings suggest that thyrocytes can be activated by GD-IgG and IGF-1 to express powerful T cell chemoattractants. These actions of GD-IgG appear to be mediated through pathways independent of TSHR. Thus in GD, thyrocytes may participate directly in lymphocyte recruitment through their expression of IL-16 and RANTES.




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