TIM-4 Has Dual Function in the Induction and Effector Phases of Murine Arthritis
TIM-4 Has Dual Function in the Induction and Effector Phases of Murine Arthritis
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DOI：
10.4049/jimmunol.1203035
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发表时间：
2013-11-01
影响因子：
4.4
通讯作者：
Akiba, Hisaya
中科院分区：
文献类型：
--
作者：
Abe, Yoshiyuki;Kamachi, Fumitaka;Akiba, Hisaya
T细胞IG和粘蛋白结构域（TIM）-4参与免疫调节。然而，TIM-4的病理功能尚未被理解，并且在各种疾病模型中仍有待阐明。在这项研究中，DBA/1小鼠在胶原诱导的关节炎（CIA）的诱导或效应阶段用抗TIM-4 mAb治疗。在诱导阶段抗TIM-4治疗加剧了CIA的发展。体外实验表明，CD 4 T细胞与APC上的TIM-4结合，从而诱导对CD 4 T细胞的抑制作用。相反，在CIA发作前或发作后或甚至在CIA晚期用抗TIM-4 mAb治疗，通过减少踝关节中的促炎细胞因子而不影响T或B细胞应答，显著抑制了CIA的发展和进展。一致地，在抗TIM-4处理的小鼠中，胶原蛋白Ab诱导的关节炎的临床关节炎评分（其不由T或B细胞介导）显著降低，同时关节中促炎细胞因子减少。在体外，巨噬细胞分泌促炎细胞因子响应TIM-4-IG蛋白和LPS，这是由抗TIM-4单克隆抗体减少。抗TIM-4单克隆抗体还抑制破骨细胞的分化和骨吸收活性。这些结果表明，TIM-4有两个不同的功能，这取决于关节炎的阶段。抗TIM-4 mAb对关节炎的治疗作用是通过抑制炎性细胞产生促炎细胞因子、破骨细胞分化和骨吸收介导的，这表明TIM-4可能是关节炎治疗的合适靶点。
T cell Ig and mucin domain (TIM)-4 is involved in immune regulation. However, the pathological function of TIM-4 has not been understood and remains to be clarified in various disease models. In this study, DBA/1 mice were treated with anti-TIM-4 mAb during the induction or effector phase of collagen-induced arthritis (CIA). Anti-TIM-4 treatment in the induction phase exacerbated the development of CIA. In vitro experiments suggest that CD4 T cells bind to TIM-4 on APCs, which induces inhibitory effect to CD4 T cells. In contrast, therapeutic treatment with anti-TIM-4 mAb just before or after the onset or even at later stage of CIA significantly suppressed the development and progression by reducing proinflammatory cytokines in the ankle joints without affecting T or B cell responses. Consistently, clinical arthritis scores of collagen Ab-induced arthritis, which is not mediated by T or B cells, were significantly reduced in anti-TIM-4-treated mice with a concomitant decrease of proinflammatory cytokines in the joints. In vitro, macrophages secreted proinflammatory cytokines in response to TIM-4-Ig protein and LPS, which were reduced by the anti-TIM-4 mAb. The anti-TIM-4 mAb also inhibited the differentiation and bone-resorbing activity of osteoclasts. These results indicate that TIM-4 has two distinct functions depending on the stage of arthritis. The therapeutic effect of anti-TIM-4 mAb on arthritis is mediated by the inhibition of proinflammatory cytokine production by inflammatory cells, osteoclast differentiation, and bone resorption, suggesting that TIM-4 might be an appropriate target for the therapeutic treatment of arthritis.