Receptor-interacting protein 2 gene silencing attenuates allergic airway inflammation

Persistent activation of NF-κB has been associated with the development of asthma. Receptor-interacting protein 2 (Rip2) is a transcriptional product of NF-κB activation. It is an adaptor protein with serine/threonine kinase activity and has been shown to positively regulate NF-κB activity. We inves...

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Published in:	The Journal of immunology (1950) Vol. 191; no. 5; pp. 2691 - 2699
Main Authors:	Goh, Fera Y, Cook, Katrina L T P, Upton, Nadine, Tao, Lin, Lah, Lin Chin, Leung, Bernard P, Wong, W S Fred
Format:	Journal Article
Language:	English
Published:	United States 01-09-2013
Subjects:	Animals Asthma - immunology Asthma - metabolism Disease Models, Animal Female Gene Silencing Hypersensitivity - immunology Hypersensitivity - metabolism Immunoblotting Mice Mice, Inbred BALB C NF-kappa B - immunology NF-kappa B - metabolism Pneumonia - immunology Pneumonia - metabolism Receptor-Interacting Protein Serine-Threonine Kinases - immunology Receptor-Interacting Protein Serine-Threonine Kinases - metabolism Respiratory Hypersensitivity - immunology Respiratory Hypersensitivity - metabolism RNA, Small Interfering
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Summary:	Persistent activation of NF-κB has been associated with the development of asthma. Receptor-interacting protein 2 (Rip2) is a transcriptional product of NF-κB activation. It is an adaptor protein with serine/threonine kinase activity and has been shown to positively regulate NF-κB activity. We investigated potential protective effects of Rip2 gene silencing using small interfering RNA (siRNA) in an OVA-induced mouse asthma model. Rip2 protein level was found to be upregulated in allergic airway inflammation. A potent and selective Rip2 siRNA given intratracheally knocked down Rip2 expression in OVA-challenged lungs and reduced OVA-induced increases in total and eosinophil counts, and IL-4, IL-5, IL-13, IL-1β, IL-33, and eotaxin levels in bronchoalveolar lavage fluid. Rip2 silencing blocked OVA-induced inflammatory cell infiltration and mucus hypersecretion as observed in lung sections, and mRNA expression of ICAM-1, VCAM-1, E-selectin, RANTES, IL-17, IL-33, thymic stromal lymphopoietin, inducible NO synthase, and MUC5ac in lung tissues. In addition, elevation of serum OVA-specific IgE level in mouse asthma model was markedly suppressed by Rip2 siRNA, together with reduced IL-4, IL-5, and IL-13 production in lymph node cultures. Furthermore, Rip2 siRNA-treated mice produced significantly less airway hyperresponsiveness induced by methacholine. Mechanistically, Rip2 siRNA was found to enhance cytosolic level of IκBα and block p65 nuclear translocation and DNA-binding activity in lung tissues from OVA-challenged mice. Taken together, our findings clearly show that knockdown of Rip2 by gene silencing ameliorates experimental allergic airway inflammation, probably via interruption of NF-κB activity, confirming Rip2 a novel therapeutic target for the treatment of allergic asthma.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.1202416