methimazole and Virus-Diseases

Toll-like receptors (TLRs) initiate an innate immune response. TLR3 on dendritic cells recognize double-stranded (ds) RNA and 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 Fisher rat thyroid cell line-5 (FRTL-5) thyroid cells and are functional because incubating cells with polyinosine-polycytidylic acid causes 1) transcriptional activation of both the nuclear factor kappaB (NF-kappaB)/Elk1 and interferon (IFN) regulatory factor-3/IFN-beta signal paths, 2) posttranscriptional activation of NF-kappaB and ERK1/2, and 3) increased IFN-beta mRNA. TLR3 can be overexpressed, along with dsRNA-dependent protein kinase, major histocompatibility complex-I or II, and IFN regulatory factor-1, by transfecting dsRNA into the cells, infection with Influenza A virus, or incubation with IFN-beta, but not by incubation with dsRNA or IFNgamma, or by dsDNA transfection. A methimazole (MMI) derivative, phenylmethimazole, to a significantly greater degree than MMI, prevents overexpression by inhibiting increased transcriptional activation of IRF-3 and of IFN-stimulated response elements, phosphorylation of signal transducers and activation of transcription (STAT-1), but not NF-kappaB activation. TLR3 can be functionally overexpressed in cultured human thyrocytes by dsRNA transfection or IFN-beta treatment. Immunohistochemical studies show that 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 phenylmethimazole to a significantly greater extent than MMI by inhibiting only the IFN regulatory factor-3/IFN-beta/signal transducers and activation of transcription 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.

Topics: Animals; Chemokines, CC; Gene Expression; Humans; Influenza A virus; Interferon-beta; Membrane Glycoproteins; Methimazole; Mice; Rats; Receptors, Cell Surface; RNA, Double-Stranded; RNA, Messenger; Signal Transduction; Thiones; Thyroid Gland; Thyroiditis, Autoimmune; Toll-Like Receptor 3; Toll-Like Receptors; Transfection; Virus Diseases

A population of patients with agranulocytosis admitted to a general hospital over a period of 12 yr was studied retrospectively in order to determine the causes of the disease. Of the 48 cases identified, 31 (65%) had drug-induced neutropenia, whereas 17 (35%) had chronic neutropenia unrelated to the use of drugs. Eight patients had an underlying hematological malignancy. Patients with agranulocytosis not induced by drugs more frequently had hepatomegaly, splenomegaly, enlarged lymph glands, or thrombocytopenia together with severe anemia. In contrast, drug-induced agranulocytosis was more severe, with a higher incidence of positive blood cultures, low cellularity of initial bone marrow aspirates, and a shorter duration of neutropenia. Dipyrone and methimazole were the drugs most commonly associated with agranulocytosis. Dipyrone was probably the causative agent in two of the seven drug-induced fatalities. In view of these findings, and those of several previous reports, it is proposed that the use of dipyrone in Israel be severely restricted or discontinued altogether.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Aminopyrine; Anti-Bacterial Agents; Antineoplastic Agents; Bacterial Infections; Blood Cell Count; Bone Marrow Examination; Child; Child, Preschool; Dipyrone; Female; Humans; Israel; Leukemia; Lymphoma; Male; Methimazole; Middle Aged; Retrospective Studies; Tranquilizing Agents; Virus Diseases