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Submitted on March 9, 2004
Accepted on January 10, 2005
Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA; Medstar Research Institute, Washington Hospital Center, Washington DC 20010, USA; The Ohio State University, Arthur G. James Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210, USA; Section of Endocrinology, Department of Science of Aging, Università degli Studi "G.D. Annunzio", Faculty of Medicine and Surgery, 66100 Chieti, Italy; The Department of Chemical Engineering; Ohio University; Athens, OH 45701; The Department of Biomedical Sciences, College of Osteopathic Medicine; Ohio University; Athens, OH 45701
Toll-like receptors (TLRs) initiate an innate immune response. TLR3 on dendritic cells recognize dsRNA, then signal increases in cytokines and recognition molecules important for immune cell interactions. In this report, we demonstrate TLR3 mRNA and protein are expressed on rat FRTL-5 thyroid cells and are functional, since incubating cells with Poly (I:C) causes (i) transcriptional activation of both the NF-
B/Elk1 and IRF-3/IFN-
signal paths, (ii) post transcriptional activation of NF-B and ERK1/2, and (iii) increased IFN- mRNA. TLR3 can be overexpressed, along with PKR, major histocompatibility complex (MHC)-I or II, and IRF-1, by transfecting dsRNA into the cells, infection with Influenza A virus, or incubation with IFN-, but not by incubation with dsRNA or IFN
, or by dsDNA transfection. A methimazole (MMI) derivative, phenylmethimazole (C10), to a significantly greater degree than MMI, prevents overexpression by inhibiting increased transcriptional activation of IRF-3 and ISREs, STAT phosphorylation, but not NF-B activation. TLR3 can be functionally overexpressed in cultured human thyrocytes by dsRNA transfection or IFN- treatment. Immunohistochemical studies show TLR3 protein is overexpressed in human thyrocytes surrounded by immune cells in 100% of patients with Hashimoto's thyroiditis examined, but not in normal or Graves' thyrocytes. We conclude that functional TLR3 are present on thyrocytes; TLR3 downstream signals can be overexpressed by pathogen-related stimuli; overexpression can be reversed by C10 to a significantly greater extent than MMI by inhibiting only the IRF-3/IFN-/STAT arm of the TLR3 signal system; and TLR3 overexpression can induce an innate immune response in thyrocytes which may be important in the pathogenesis of Hashimoto's thyroiditis and in the immune cell infiltrates.
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