title: Glycyrrhizin, a Direct HMGB1 Antagonist, Ameliorates Inflammatory Infiltration in a Model of Autoimmune Thyroiditis via Inhibition of TLR2-HMGB1 Signaling.
abstract: High mobility group box-1 (HMGB1), a non-histone protein, plays an important role in autoimmune diseases. However, the significance of HMGB1 in the pathogenesis of autoimmune thyroiditis has not been reported. The purpose of this study was to explore whether HMGB1 participates in the pathogenesis of autoimmune thyroiditis, and whether glycyrrhizin (GL), a direct inhibitor of HMGB1, attenuates the severity of thyroid inflammatory infiltration in a murine model of autoimmune thyroiditis.
  
  
  
  A total of 80 male NOD.H-2h4mice were randomly divided into a control or iodine supplement (NaI) group at four weeks of age, and the control group was fed with regular water, whereas the NaI group was supplied with 0.005% sodium iodine water. Another 24 male NOD.H-2h4mice were also randomized into three groups (eight mice per group) as follows: control, NaI, and GL treatment after iodine supplementation (NaI + GL). The NOD.H-2h4mice were fed with 0.005% sodium iodide water for eight weeks to enhance autoimmune thyroiditis. After iodine treatment, the mice received intraperitoneal injections of GL for four weeks. The severity of lymphocytic infiltration in the thyroid gland was measured by histopathological studies. The serum levels of HMGB1, tumor necrosis factor alpha, interleukin (IL)-6, IL-1β, and thyroglobulin antibody titers were measured using an enzyme-linked immunosorbent assay. HMGB1 expression was measured by immunohistochemical staining and real-time polymerase chain reaction. TLR2, HMGB1, MyD88, and nuclear transcription factor κB were measured by Western blot.
  
  
  
  The mRNA expression of HMGB1 was significantly higher at 8 and 16 weeks in the NaI group than it was in the control group. Serum levels of thyroglobulin antibodies, HMGB1, tumor necrosis factor alpha, IL-6, and IL-1β were significantly increased in the NaI group, but they were dramatically attenuated with GL injection. The prevalence of thyroiditis and the infiltration of lymphocytes were significantly decreased in the NaI + GL group. GL administration also significantly reduced the protein expression of TLR2, MyD88, HMGB1 and nuclear transcription factor κB in the thyroid gland and attenuated the severity of thyroiditis.
  
  
  
  HMGB1 may play a crucial role in autoimmune thyroiditis by causing inflammatory infiltration, thus increasing the severity of autoimmune thyroiditis. GL effectively attenuated thyroiditis in the iodine-induced NOD.H-2h4mice via a molecular mechanism related to the inhibition of TLR2-HMGB1 signaling.
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Chenyan
authors.initials: C
authors.lastname: Li
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Shiqiao
authors.initials: S
authors.lastname: Peng
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .|2 Department of Intensive Care Unit, Affiliated Hospital of Qingdao University , Qingdao, People's Republic of China .
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Cheng
authors.initials: C
authors.lastname: Han
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .|3 Department of Laboratory Medicine, The First Hospital of China Medical University , Shenyang, People's Republic of China .
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .|4 Department of Endocrinology, Sir Run Run Shaw Hospital, Affiliated to School of Medicine, Zhejiang University , Hangzhou, People's Republic of China .
authors.forename: Ting
authors.initials: T
authors.lastname: Jin
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .|5 Department of Emergency, People's Liberation Army No.202 Hospital , Shenyang, People's Republic of China .
authors.forename: Shanshan
authors.initials: S
authors.lastname: Liu
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Xie
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Xue
authors.initials: X
authors.lastname: He
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Hanyi
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Ling
authors.initials: L
authors.lastname: Shan
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Chenling
authors.initials: C
authors.lastname: Fan
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Zhongyan
authors.initials: Z
authors.lastname: Shan
authors.affiliation: 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University , Shenyang, People's Republic of China .
authors.forename: Weiping
authors.initials: W
authors.lastname: Teng
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D019695:Glycyrrhizic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012974:Sodium Iodide; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013967:Thyroiditis, Autoimmune / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D019695:Glycyrrhizic Acid; D012974:Sodium Iodide
keywords: HMGB1; NOD.H-2h4 mice; TLR; autoimmune thyroiditis; glycyrrhizin