Immunoglobulin G from patients with Graves' disease induces interleukin-16 and RANTES expression in cultured human thyrocytes: a putative mechanism for T-cell infiltration of the thyroid in autoimmune disease.
Mechanisms underlying lymphocyte infiltration of the thyroid gland and orbit in Graves' disease (GD) are poorly understood. The IGF-I receptor (IGF-IR) is a newly recognized self-antigen that, when activated in GD fibroblasts by IGF-I or GD-IgGs, provokes the expression of IL-16 and RANTES (regulated upon activation, normal T cell expressed and secreted)-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-I 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. Rapamycin, a specific inhibitor of the FRAP/mammalian target of rapamycin/p70(s6k) pathway, prevented GD-IgG-provoked IL-16 synthesis. IH7, a monoclonal antibody directed at IGF-IR also blocked the induction of chemoattraction as well as RANTES mRNA synthesis. Our findings suggest that thyrocytes can be activated by GD-IgG and IGF-I to express powerful T-cell chemoattractants. These actions of GD-IgG appear to be mediated through pathways independent of the TSH receptor. Thus, in GD, thyrocytes may participate directly in lymphocyte recruitment through their expression of IL-16 and RANTES.
Gianoukakis
Andrew G
AG
Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California 90502, USA.
Douglas
Raymond S
RS
King
Chris S
CS
Cruikshank
William W
WW
Smith
Terry J
TJ
D000911:Antibodies, Monoclonal / Q000276:immunology; D001327:Autoimmune Diseases / Q000473:pathology*; D002465:Cell Movement; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D006111:Graves Disease / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D019410:Interleukin-16 / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000032:analysis; D011989:Receptors, Thyrotropin / Q000032:analysis; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000502:physiology*; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology
D000911:Antibodies, Monoclonal; D018946:Chemokine CCL5; D007074:Immunoglobulin G; D019410:Interleukin-16; D012333:RNA, Messenger; D011989:Receptors, Thyrotropin; D003907:Dexamethasone; D017526:Receptor, IGF Type 1; D020123:Sirolimus