A Rac1 inhibitory peptide suppresses antibody production and paw swelling in the murine collagen-induced arthritis model of rheumatoid arthritis
A Rac1 inhibitory peptide suppresses antibody production and paw swelling in the murine collagen-induced arthritis model of rheumatoid arthritis
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DOI：
10.1186/ar2900
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发表时间：
2010-01-01
影响因子：
4.9
通讯作者：
Tak, Paul P.
中科院分区：
文献类型：
--
作者：
Abreu, Joana R. F.;Dontje, Wendy;Tak, Paul P.
简介：Rho 家族 GTPase Rac1 调节细胞骨架重排，这对于炎症部位白细胞的募集、外渗和激活至关重要。 Rac1 信号传导还促进淋巴细胞和破骨细胞的激活和存活。因此，我们评估了细胞渗透性 Rac1 羧基末端抑制肽调节胶原诱导性关节炎 (CIA) 小鼠疾病的能力。方法：在 DBA/1 小鼠中诱导 CIA，在早期或慢性疾病中，通过腹腔注射对照肽或 Rac1 抑制肽每周 3 次对小鼠进行治疗。通过测量爪肿胀来评估对疾病进展的影响。通过组织学和放射学检查炎症和关节破坏。通过酶联免疫吸附测定法测量抗II型胶原抗体的血清水平。通过荧光激活细胞分选分析评估 T 细胞表型和激活。使用Mann-Whitney U 和未配对的Student t 检验对结果进行分析。结果：用Rac1 抑制肽治疗小鼠可减少早期疾病中的爪肿胀，并且在更慢性的关节炎中减少一定程度的爪肿胀。有趣的是，虽然 Rac1 抑制肽不会影响关节破坏，但在早期和慢性关节炎中，接受治疗的小鼠中抗 II 型胶原抗体的产生显着减少。体外，Rac1 抑制肽抑制 T 细胞受体/CD28 依赖性肿瘤坏死因子 a、干扰素的产生。和白细胞介素 17 被来自胶原蛋白引发的小鼠的 T 细胞所抑制，并减少了 ICOS 和 CD154（对 B 细胞帮助很重要的 T 细胞共刺激蛋白）的诱导。结论：数据表明，用 Rac1 羧基末端抑制肽靶向 Rac1 可能会抑制自身免疫性疾病中的 T 细胞激活和自身抗体产生。这是否可以转化为具有临床意义的改善仍有待证明。
Introduction: The Rho family GTPase Rac1 regulates cytoskeletal rearrangements crucial for the recruitment, extravasation and activation of leukocytes at sites of inflammation. Rac1 signaling also promotes the activation and survival of lymphocytes and osteoclasts. Therefore, we assessed the ability of a cell-permeable Rac1 carboxy-terminal inhibitory peptide to modulate disease in mice with collagen-induced arthritis (CIA).Methods: CIA was induced in DBA/1 mice, and in either early or chronic disease, mice were treated three times per week by intraperitoneal injection with control peptide or Rac1 inhibitory peptide. Effects on disease progression were assessed by measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology. Serum levels of anti-collagen type II antibodies were measured by enzyme-linked immunosorbent assay. T-cell phenotypes and activation were assessed by fluorescence-activated cell sorting analysis. Results were analyzed using Mann-Whitney U and unpaired Student t tests.Results: Treatment of mice with Rac1 inhibitory peptide resulted in a decrease in paw swelling in early disease and to a lesser extent in more chronic arthritis. Of interest, while joint destruction was unaffected by Rac1 inhibitory peptide, anti-collagen type II antibody production was significantly diminished in treated mice, in both early and chronic arthritis. Ex vivo, Rac1 inhibitory peptide suppressed T-cell receptor/CD28-dependent production of tumor necrosis factor a, interferon. and interleukin-17 by T cells from collagen-primed mice, and reduced induction of ICOS and CD154, T-cell costimulatory proteins important for B-cell help.Conclusions: The data suggest that targeting of Rac1 with the Rac1 carboxy-terminal inhibitory peptide may suppress T-cell activation and autoantibody production in autoimmune disease. Whether this could translate into clinically meaningful improvement remains to be shown.