title: Receptor-interacting protein 2 gene silencing attenuates allergic airway inflammation.
abstract: 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.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore 119228.
authors.forename: Fera Y
authors.initials: FY
authors.lastname: Goh
authors.forename: Katrina L T P
authors.initials: KL
authors.lastname: Cook
authors.forename: Nadine
authors.initials: N
authors.lastname: Upton
authors.forename: Lin
authors.initials: L
authors.lastname: Tao
authors.forename: Lin Chin
authors.initials: LC
authors.lastname: Lah
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Leung
authors.forename: W S Fred
authors.initials: WS
authors.lastname: Wong
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D034741:RNA, Small Interfering; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse