Transforming growth factor-beta has contrasting effects in the presence or absence of exogenous interleukin-12 on the in vitro activation of cells that transfer experimental autoimmune thyroiditis.
Mouse thyroglobulin (MuTg)-sensitized spleen cells activated in vitro with MuTg induce experimental autoimmune thyroiditis (EAT) in recipient mice with a thyroid infiltrate consisting primarily of lymphocytes. A more severe and histologically distinct granulomatous form of EAT (G-EAT) is induced when donor cells are activated with MuTg together with anti-interferon-gamma (IFN-gamma), anti-interleukin-2 receptor (IL-2R) monoclonal antibody (mAb), and IL-12. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that can both suppress and exacerbate autoimmune diseases and often has inhibitory effects on lymphocytes. To determine if TGF-beta could modulate the in vitro activation of effector cells for G-EAT, TGF-beta was added to cultures of MuTg-sensitized donor spleen cells together with MuTg. Cells activated in the presence of 2 ng/ml TGF-beta induced moderately severe G-EAT in recipient mice. G-EAT induced by cells activated in the presence of TGF-beta was histologically similar but less severe than the G-EAT induced by cells activated in the presence of IL-12. IL-12 and TGF-beta modulate the activation of G-EAT effector cells by distinct mechanisms, as cells activated by TGF-beta could induce G-EAT in the presence of anti-IL-12, and TGF-beta inhibited the effects of IL-12 on EAT effector cells. TGF-beta exerted its activity during the first 24 h of the 72-h culture, whereas IL-12 functioned primarily during the final 24 h of culture. These results indicate that thyroid lesions with granulomatous histopathology can be induced by both IL-12-dependent and IL-12-independent mechanisms, and TGF-beta can exert both positive and negative effects on the effector cells for G-EAT.
Fondal
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Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212, USA.
Sampson
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Sharp
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Braley-Mullen
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D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006099:Granuloma / Q000276:immunology / Q000473:pathology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008808:Mice, Inbred CBA; D012333:RNA, Messenger / Q000096:biosynthesis; D013154:Spleen / Q000637:transplantation*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013954:Thyroglobulin / Q000276:immunology; D013967:Thyroiditis, Autoimmune / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D013954:Thyroglobulin