King's College London

TY - JOUR

T1 - Receptor-Interacting Protein 2 Gene Silencing Attenuates Allergic Airway Inflammation

AU - Goh, Fera Y.

AU - Cook, Katrina L. T. P.

AU - Upton, Nadine

AU - Tao, Lin

AU - Lah, Lin Chin

AU - Leung, Bernard P.

AU - Wong, W. S. Fred

PY - 2013/9/1

Y1 - 2013/9/1

N2 - Persistent activation of NF-kappa B has been associated with the development of asthma. Receptor-interacting protein 2 (Rip2) is a transcriptional product of NF-kappa B activation. It is an adaptor protein with serine/threonine kinase activity and has been shown to positively regulate NF-kappa B 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-1 beta, 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 I kappa B alpha 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-kappa B activity, confirming Rip2 a novel therapeutic target for the treatment of allergic asthma.

AB - Persistent activation of NF-kappa B has been associated with the development of asthma. Receptor-interacting protein 2 (Rip2) is a transcriptional product of NF-kappa B activation. It is an adaptor protein with serine/threonine kinase activity and has been shown to positively regulate NF-kappa B 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-1 beta, 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 I kappa B alpha 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-kappa B activity, confirming Rip2 a novel therapeutic target for the treatment of allergic asthma.

KW - NF-KAPPA-B

KW - THYMIC STROMAL LYMPHOPOIETIN

KW - EPITHELIAL-CELLS

KW - SMOOTH-MUSCLE

KW - NITRIC-OXIDE

KW - IMMUNE-SYSTEM

KW - MAST-CELLS

KW - TNF-ALPHA

KW - ASTHMA

KW - ACTIVATION

U2 - 10.4049/jimmunol.1202416

DO - 10.4049/jimmunol.1202416

M3 - Article

VL - 191

SP - 2691

EP - 2699

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

M1 - N/A

ER -