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Published online before print October 17, 2006

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(Journal of Leukocyte Biology. 2007;81:306-314.)
© 2007 by Society for Leukocyte Biology

Decreasing TNF- results in less fibrosis and earlier resolution of granulomatous experimental autoimmune thyroiditis

Kemin Chen^*,1,2, Yongzhong Wei^*,1, Gordon C. Sharp^*, and Helen Braley-Mullen^*,,

^* Departments of Internal Medicine,
Pathology, and
Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA; and
VA Research Service, Columbia, Missouri, USA

²Correspondence: Division of Immunology and Rheumatology, Dept. of Medicine, University of Missouri, M306 Medical Sciences, One Hospital Dr., Columbia, MO 65212, USA. E-mail: chenk{at}health.missouri.edu

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced in DBA/1 mice by adoptive transfer of mouse thyroglobulin (MTg)-primed spleen cells. TNF- is an important proinflammatory cytokine and apoptotic molecule involved in many autoimmune diseases. To study its role in G-EAT, anti-TNF- mAb was given to recipient mice. Disease severity was comparable between mice with or without anti-TNF- treatment at days 19–21, the time of maximal severity of G-EAT, suggesting TNF- is not essential for development of thyroid inflammation. However, thyroid lesions resolved at day 48 in anti-TNF--treated mice, while thyroids of rat Ig-treated controls had fibrosis. These results suggested that reducing TNF- contributed to resolution of inflammation and inhibited fibrosis. Gene and protein expression of inflammatory molecules was examined by RT-PCR and immunostaining, and apoptosis was detected using TUNEL staining and an apoptosis kit. Thyroids of anti-TNF--treated controls had reduced proinflammatory and profibrotic molecules, e.g., IFN-, IL-1ß, IL-17, inducible NOS and MCP-1, at day 19 compared with thyroids of rat Ig-treated mice. There were more apoptotic thyrocytes in rat Ig-treated controls than in anti-TNF--treated mice. The site of expression of the anti-apoptotic molecule FLIP also differed between rat Ig-treated and anti-TNF--treated mice. FLIP was predominantly expressed by inflammatory cells of rat Ig-treated mice and by thyrocytes of anti-TNF--treated mice. These results suggest that anti-TNF- may regulate expression of proinflammatory cytokines and apoptosis in thyroids, resulting in less inflammation, earlier resolution, and reduced fibrosis.

Key Words: rodent • autoimmunity • cytokines

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