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首页> 外文期刊>Biochemical Pharmacology >Inhibition of p21-activated kinase 1 attenuates the cardinal features of asthma through suppressing the lymph node homing of dendritic cells
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Inhibition of p21-activated kinase 1 attenuates the cardinal features of asthma through suppressing the lymph node homing of dendritic cells

机译：P21活化激酶1的抑制通过抑制树突细胞的淋巴结归巢，衰减哮喘的基本特征

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摘要

Dendritic cell (DC) trafficking from lung to the draining mediastinal lymph nodes (MLNs) is a key step for initiation of T cell responses in allergic asthma. In the present study, we investigate the role of DC-mediated airway inflammation after inhibition of p21- activated kinase 1 (PAK1), an effector of Rac and Cdc42 small GTPases, in the allergen-induced mouse models of asthma. Systemic administration of PAK1 specific inhibitor IPA-3 significantly attenuates not only the airway inflammation but also the airway hyperresponsiveness in a mouse model of ovalbumin-induced asthma. Specifically, intratracheal administration of low dosage of IPA-3 consistently decreases not only the airway inflammation but also the DC trafficking from lung to the MLNs. Importantly, intratracheal instillation of IPA-3-treated and ovalbumin-pulsed DCs behaves largely the same as that of either Rac inhibitor-treated and ovalbumin-pulsed DCs or Cdc42 inhibitor-treated and ovalbumin-pulsed DCs in attenuation of the airway inflammation in ovalbumin challenged mice. Mechanistically, PAK1 is not involved in the maturation, apoptosis, antigen uptake, and T cell activation of cultured DCs, but PAK1 dose lie on the downstream of Rac and Cdc42 to regulate the DC migration toward the chemokine C-C motif chemokine ligand 19. Taken together, this study demonstrates that inhibition of PAK1 attenuates the cardinal features of asthma through suppressing the DC trafficking from lung to the MLN, and that interfere with DC trafficking by a PAK1 inhibitor thus holds great promise for the therapeutic intervention of allergic diseases.
机译：从肺部到排出的纵隔淋巴结（MLNS）的树突状细胞（DC）是用于在过敏性哮喘中引发T细胞应答的关键步骤。在本研究中，我们研究了在过敏原诱导的哮喘小鼠模型中抑制P21-活化激酶1（PAK1），RAC和CDC42小GTP酶的效应器后的DC介导的气道炎症的作用。 PAK1特异性抑制剂IPA-3的全身施用不仅显着减弱了气道炎症，而且显着衰减，而且显着衰减，而且还显着减轻了卵泡诱导的哮喘的小鼠模型中的气道高反应性。具体地，IPA-3的低剂量腹腔内施用不仅可以减少气道炎症，而且始终降低了从肺部到MLNS的DC贩运。重要的是，IPA-3处理和卵磷蛋白脉冲DC的肿瘤内滴注物的表现在很大程度上与RAC抑制剂处理的和卵泡 - 脉冲DC或CDC42抑制剂处理的和卵磷蛋白脉冲DC在卵磷酶中的气道炎症的衰减中相同挑战的老鼠。机械地，PAK1没有参与培养的DC的成熟，凋亡，抗原摄取和T细胞活化，但PAK1剂量位于RAC和CDC42的下游，以调节趋向趋化因子CC MOTIF趋化因子19的DC迁移该研究表明，PAK1的抑制通过抑制从肺部到MLN的DC贩运的DC抑制哮喘的基本特征，并且干扰PAK1抑制剂的DC贩运因此对过敏性疾病的治疗干预造成了巨大的承诺。

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  • 来源
    《Biochemical Pharmacology》 |2018年第2018期|共10页
  • 作者

    Lu Meiping; Xu Chengyun; Zhang Qin; Wu Xiling; Tang Lanfang; Wang Xiangzhi; Wu Junsong; Wu Ximei;

  • 作者单位

    Zhejiang Univ Childrens Hosp Sch Med Dept Allergy Immunol &

    Rheumatol Hangzhou 310052 Zhejiang;

    Zhejiang Univ Sch Med Dept Pharmacol 866 Yuhangtang Rd Hangzhou 310058 Zhejiang Peoples R;

    Zhejiang Univ Sch Med Dept Pharmacol 866 Yuhangtang Rd Hangzhou 310058 Zhejiang Peoples R;

    Zhejiang Univ Sch Med Childrens Hosp Dept Resp Med Hangzhou 310052 Zhejiang Peoples R China;

    Zhejiang Univ Sch Med Childrens Hosp Dept Resp Med Hangzhou 310052 Zhejiang Peoples R China;

    Zhejiang Univ Sch Med Childrens Hosp Dept Resp Med Hangzhou 310052 Zhejiang Peoples R China;

    Zhejiang Univ Sch Med Affiliated Hosp 1 Dept Orthoped Surg Hangzhou 310009 Zhejiang Peoples R;

    Zhejiang Univ Sch Med Dept Pharmacol 866 Yuhangtang Rd Hangzhou 310058 Zhejiang Peoples R;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    p21-Activated kinase 1; Dendritic cells; Lymph node; Asthma; Cell migration;

    机译：p21-活化激酶1;树突细胞;淋巴结;哮喘;细胞迁移;

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