Haga Takaaki, Suzuki Jun-Ichi, Kosuge Hisanori, Ogawa Masahito, Saiki Hitoshi, Haraguchi Go, Maejima Yasuhiro, Isobe Mitsuaki, Uede Toshimitsu
Department of Cardiovascular Medicine Tokyo Medical and Dental University 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
J Mol Cell Cardiol. 2009 May;46(5):719-27. doi: 10.1016/j.yjmcc.2009.02.003. Epub 2009 Feb 20.
4-1BB, a member of the tumor necrosis factor receptor (TNFR) family, binds the 4-1BB ligand (4-1BBL), works as a costimulatory molecule, and regulates T cell-mediated immune responses. Although inflammation is an essential pathological feature of myocarditis, the role of 4-1BB in experimental autoimmune myocarditis (EAM) remains unclear. Lewis rats were immunized on day 0 with purified porcine cardiac myosin to establish EAM. 4-1BB-immunoglobulin (4-1BBIg) was administered intraperitoneally (n=6) a total of 9 times (3 times per week). Rats were killed on day 21 to study effects of 4-1BB/4-1BBL pathway blockade. For controls, isotype-matched human IgG was administered in other EAM rats (n=6). Histologic and echocardiographic examination showed development of EAM attenuated by 4-1BBIg. Suppression of mRNA expression for IL-1alpha, IL-1beta, IL-4, IL-6, and TNF-alpha was noted in the heart tissue treated with 4-1BBIg. Treatment with 4-1BBIg reduced production of Th1-type cytokines, and inhibited T cell proliferation in vitro. In the 4-1BB signaling pathway in splenocytes, 4-1BBIg suppressed JNK, p38, and IkappaB activity but not that of ERK1/2. Blockade of T cell activation through the 4-1BB/4-1BBL pathway regulates development of EAM; therefore, 4-1BB may be an effective target for treating myocarditis.
4-1BB是肿瘤坏死因子受体（TNFR）家族的成员，可与4-1BB配体（4-1BBL）结合，作为共刺激分子发挥作用，并调节T细胞介导的免疫反应。尽管炎症是心肌炎的一个重要病理特征，但4-1BB在实验性自身免疫性心肌炎（EAM）中的作用仍不清楚。在第0天用纯化的猪心肌肌球蛋白免疫Lewis大鼠以建立EAM。腹腔注射4-1BB免疫球蛋白（4-1BBIg）（n = 6），共9次（每周3次）。在第21天处死大鼠，以研究4-1BB/4-1BBL途径阻断的作用。作为对照，在其他EAM大鼠（n = 6）中给予同型匹配的人IgG。组织学和超声心动图检查显示，4-1BBIg减轻了EAM的发展。在用4-1BBIg处理的心脏组织中，观察到IL-1α、IL-1β、IL-4、IL-6和TNF-α的mRNA表达受到抑制。4-1BBIg处理可减少Th1型细胞因子的产生，并在体外抑制T细胞增殖。在脾细胞的4-1BB信号通路中，4-1BBIg抑制JNK、p38和IkappaB的活性，但不抑制ERK1/2的活性。通过4-1BB/4-1BBL途径阻断T细胞活化可调节EAM的发展；因此，4-1BB可能是治疗心肌炎的有效靶点。
