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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.
Lu, Meiping; Xu, Chengyun; Zhang, Qin; Wu, Xiling; Tang, Lanfang; Wang, Xiangzhi; Wu, Junsong; Wu, Ximei.
Afiliación
  • Lu M; Department of Allergy immunology and rheumatology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China. Electronic address: meipinglu@zju.edu.cn.
  • Xu C; Department of Pharmacology and Key Laboratory of CFDA for Respiratory Drug Research, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • Zhang Q; Department of Pharmacology and Key Laboratory of CFDA for Respiratory Drug Research, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • Wu X; Department of Respiratory Medicine, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China.
  • Tang L; Department of Respiratory Medicine, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China.
  • Wang X; Department of Respiratory Medicine, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China.
  • Wu J; Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • Wu X; Department of Pharmacology and Key Laboratory of CFDA for Respiratory Drug Research, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: xiwu@zju.edu.cn.
Biochem Pharmacol ; 154: 464-473, 2018 08.
Article en En | MEDLINE | ID: mdl-29906467
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Asma / Células Dendríticas / Quinasas p21 Activadas / Ganglios Linfáticos Límite: Animals Idioma: En Revista: Biochem Pharmacol Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Imprimir
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Asma / Células Dendríticas / Quinasas p21 Activadas / Ganglios Linfáticos Límite: Animals Idioma: En Revista: Biochem Pharmacol Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido