Division of Rheumatology, Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea.
Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, South Korea.
Cell Biol Int. 2018 Apr;42(4):393-402. doi: 10.1002/cbin.10861. Epub 2018 Jan 24.
Tacrolimus is an immunosuppressive drug that inhibits the release of inflammatory cytokines involved in rheumatoid arthritis development by blocking T cell activation. "Endoplasmic reticulum stress," an imbalance between protein folding load and capacity leading to the accumulation of unfolded proteins in the endoplasmic reticulum lumen, has been implicated in rheumatoid arthritis and other inflammatory and metabolic diseases. We aimed to investigate the effect of tacrolimus on endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation and elucidate the underlying mechanisms. In vitro studies were performed using mouse bone marrow cells that were cultured with or without interleukin-1β, thapsigargin, or tacrolimus to induce osteoclast differentiation. A mouse model of arthritis was established by immunizing mice with bovine type II collagen. Tacrolimus was orally administered to mice from day 20 to 45 following the initial immunization, and histopathological changes and expression of specific biomarkers of endoplasmic reticulum stress-mediated inflammatory signaling pathways were examined. In vitro, tacrolimus inhibited receptor activator of nuclear factor-κB ligand-mediated osteoclast formation augmented by interleukin-1β, thapsigargin, or both. Furthermore, tacrolimus inhibited glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase, inositol-requiring enzyme 1 (IRE 1), and activating transcription factor 6 (ATF6) augmented by interleukin-1β, thapsigargin, or both. Tacrolimus significantly ameliorated osteolysis and endoplasmic reticulum stress intensity in mice. Simultaneously, it reduced inflammatory cell infiltration, osteoclastogenesis, and inflammatory responses by inhibiting GRP78, IRE 1, and ATF6. These findings suggest that tacrolimus exhibits an anti-inflammation effect in rheumatoid arthritis and might inhibit joint damage progression by inhibiting endoplasmic reticulum stress.
他克莫司是一种免疫抑制剂，通过阻断 T 细胞激活来抑制参与类风湿关节炎发展的炎症细胞因子的释放。“内质网应激”是指蛋白质折叠负荷与能力之间的失衡，导致未折叠蛋白质在内质网腔中积累，与类风湿关节炎和其他炎症性及代谢性疾病有关。我们旨在研究他克莫司对内质网应激介导的破骨细胞形成和炎症的影响，并阐明其潜在机制。在体外研究中，使用培养有白细胞介素-1β、他普西醌或他克莫司的小鼠骨髓细胞进行研究，以诱导破骨细胞分化。通过用牛型 II 胶原免疫小鼠建立关节炎模型。在初次免疫后第 20 至 45 天，通过口服给予他克莫司，检查内质网应激介导的炎症信号通路的特定生物标志物的组织病理学变化和表达。在体外，他克莫司抑制了由白细胞介素-1β、他普西醌或两者共同增强的核因子-κB 受体激活剂配体介导的破骨细胞形成。此外，他克莫司抑制了由白细胞介素-1β、他普西醌或两者共同增强的葡萄糖调节蛋白 (GRP78)、蛋白激酶 R 样内质网激酶、肌醇需求酶 1 (IRE 1) 和激活转录因子 6 (ATF6)。他克莫司显著改善了小鼠的骨质溶解和内质网应激强度。同时，它通过抑制 GRP78、IRE 1 和 ATF6 来减少炎症细胞浸润、破骨细胞形成和炎症反应。这些发现表明，他克莫司在类风湿关节炎中具有抗炎作用，通过抑制内质网应激可能抑制关节损伤的进展。
