title: Interleukin-12 promotes activation of effector cells that induce a severe destructive granulomatous form of murine experimental autoimmune thyroiditis.
abstract: Granulomatous inflammatory lesions are a major histopathological feature of a wide spectrum of human infectious and autoimmune diseases. Experimental autoimmune thyroiditis (EAT) with granulomatous histopathological features can be induced by mouse thyroglobulin (MTg)-sensitized spleen cells activated in vitro with MTg and anti-interleukin-2 receptor (anti-IL-2R), anti-IL-2, or anti-interferon-gamma (anti-IFN-gamma) monoclonal antibody (MAb). These studies suggested that IFN-gamma-producing T cells requiring IL-2 for growth may negatively regulate activation of granulomatous EAT effector cells. As IL-12 promotes activation of IFN-gamma-producing Th1 cells, the present study was undertaken to determine the role of IL-12 in activation of effector cells for granulomatous EAT. MTg-sensitized cells activated in vitro with MTg, anti-IL2R MAb, and IL-12 induced severe, destructive granulomatous thyroiditis with neutrophil inflammation, fibrin deposition, and necrosis. Many glands ultimately underwent atrophy and became fibrotic; some also showed fibrinoid necrosis and a mixed inflammatory cell infiltration of blood vessel walls indicative of a necrotizing vasculitis. Induction of severe granulomatous EAT by IL-12 required MTg in vitro and was unrelated to the IL-12-induced increase in IFN-gamma production. IL-12 markedly increased IFN-gamma production but did not induce a shift to a Th1-dominant phenotype, as other Th1 and Th2 cytokines were generally unaffected and both Th1 and Th2 cytokines were expressed in recipient thyroids. Addition of IL-12 or neutralization by anti-IL-12 at various times indicated that IL-12 exerted its primary effects in the final 24 hours of the 72-hour culture and was not required in recipient mice. Cells cultured with anti-IL-12, MTg, and anti-IL2R MAb transferred mild lymphocytic EAT but little or no granulomatous EAT. Thus, IL-12 profoundly regulates the in vitro activation of effector cells that induce histologically distinct autoimmune inflammatory lesions in the thyroid.
authors.affiliation: Department of Internal Medicine, University of Missouri-Columbia School of Medicine, 65212, USA. helen_mullen@muccmail.missouri.edu
authors.forename: H
authors.initials: H
authors.lastname: Braley-Mullen
authors.forename: G C
authors.initials: GC
authors.lastname: Sharp
authors.forename: H
authors.initials: H
authors.lastname: Tang
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Kyriakos
authors.forename: J T
authors.initials: JT
authors.lastname: Bickel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006099:Granuloma / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008808:Mice, Inbred CBA; D009500:Neutralization Tests; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013954:Thyroglobulin / Q000494:pharmacology; D013961:Thyroid Gland / Q000276:immunology* / Q000473:pathology; D013967:Thyroiditis, Autoimmune / Q000276:immunology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D018664:Interleukin-12; D007371:Interferon-gamma; D013954:Thyroglobulin