Liu Wenrui, Nakamura Hajime, Shioji Keisuke, Tanito Masaki, Oka Shin-ichi, Ahsan M Kaimul, Son Aoi, Ishii Yasuyuki, Kishimoto Chiharu, Yodoi Junji
Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Circulation. 2004 Sep 7;110(10):1276-83. doi: 10.1161/01.CIR.0000141803.41217.B6. Epub 2004 Aug 30.
Cardiac myosin-induced myocarditis is an experimental autoimmune myocarditis (EAM) model used to investigate autoimmunological mechanisms in inflammatory heart diseases and resembles fulminant myocarditis in humans. We investigated the therapeutic role of thioredoxin-1 (TRX-1), a redox-regulatory protein with antioxidant and antiinflammatory effects, in murine EAM.
EAM was generated in 5-week-old male BALB/c mice by immunization with porcine cardiac myosin at days 0 and 7. Recombinant human TRX-1 (rhTRX-1), C32S/C35S mutant rhTRX-1, or saline was administered intraperitoneally every second day from day 0 to 20. In addition, rabbit anti-mouse TRX-1 serum or normal rabbit serum was administered intraperitoneally on days -1, 2, and 6. Animals were euthanized on day 21. Histological analysis of the heart showed that TRX-1 significantly reduced the severity of EAM, whereas mutant TRX-1 failed to have such an effect, and anti-TRX-1 antibody enhanced the disease markedly. Immunohistochemical analysis showed that TRX-1 significantly suppressed cardiac macrophage inflammatory protein (MIP)-1alpha, MIP-2, and 8-hydroxydeoxyguanosine expression and macrophage infiltration into the heart in EAM. Although serum levels of MIP-1alpha were not suppressed by TRX-1 until day 21, both an in vitro chemotaxis chamber assay and an in vivo air pouch model showed that TRX-1 significantly suppressed MIP-1alpha- or MIP-2-induced leukocyte chemotaxis. However, real-time reverse transcription-polymerase chain reaction showed that TRX-1 failed to decrease chemokine receptor expression increased in the bone marrow cells of EAM mice.
TRX-1 attenuates EAM by suppressing chemokine expressions and leukocyte chemotaxis in mice.
心肌肌球蛋白诱导的心肌炎是一种实验性自身免疫性心肌炎（EAM）模型，用于研究炎症性心脏病的自身免疫机制，且与人类暴发性心肌炎相似。我们研究了硫氧还蛋白-1（TRX-1），一种具有抗氧化和抗炎作用的氧化还原调节蛋白，在小鼠EAM中的治疗作用。
在第0天和第7天用猪心肌肌球蛋白免疫5周龄雄性BALB/c小鼠以诱导EAM。从第0天至第20天每隔一天腹腔注射重组人TRX-1（rhTRX-1）、C32S/C35S突变型rhTRX-1或生理盐水。此外，在第-1、2和6天腹腔注射兔抗小鼠TRX-1血清或正常兔血清。在第21天对动物实施安乐死。心脏组织学分析表明，TRX-1显著降低了EAM的严重程度，而突变型TRX-1未能产生这种效果，抗TRX-1抗体则显著加重了疾病。免疫组织化学分析表明，TRX-1显著抑制了EAM中心脏巨噬细胞炎性蛋白（MIP）-1α、MIP-2和8-羟基脱氧鸟苷的表达以及巨噬细胞向心脏的浸润。尽管直到第21天TRX-1才抑制血清MIP-1α水平，但体外趋化室试验和体内气袋模型均表明，TRX-1显著抑制MIP-1α或MIP-2诱导的白细胞趋化。然而，实时逆转录-聚合酶链反应表明，TRX-1未能降低EAM小鼠骨髓细胞中增加的趋化因子受体表达。
TRX-1通过抑制小鼠趋化因子表达和白细胞趋化来减轻EAM。
