Effect of locally administered Syk siRNA on allergen-induced arthritis and asthma

• Published in: Molecular immunology 2013-01, Vol.53 (1-2), p.52-59
• Main Authors: Huang, Zhen-Yu, Kim, Moo-Kyung, Kim-Han, Tae-Hee, Indik, Zena K., Schreiber, Alan D.
• Format: Article
• Language: English
• Subjects: Allergens - immunology; Alveoli; Animals; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Asthma; Asthma - drug therapy; Blotting, Western; Bronchus; Cytokines; Female; Humans; Hypersensitivity - drug therapy; Hypersensitivity - immunology; Inflammation; Inflammatory diseases; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - immunology; Joint diseases; Limbs; Lung diseases; Male; Mice; Mice, Inbred C57BL; Pneumonia - drug therapy; Pneumonia - immunology; Protein-tyrosine kinase; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - immunology; Pulmonary inflammation; RNA, Small Interfering - therapeutic use; Signal transduction; Signal Transduction - drug effects; Signal Transduction - immunology; siRNA; Syk Kinase; Syk protein; Syk siRNA; Transfection
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2012.06.011

► Our Syk siRNA specifically decreases cellular levels of Syk kinase in vitro and in vivo. ► We examined the effect of locally administered Syk siRNA on arthritis and lung inflammation in mice. ► Direct joint injection of our Syk siRNA diminishes joint swelling in arthritic mice. ► Our Syk siRNA also reduces levels of inflammatory mediators including TNF-α, IFN-γ and IL-6 in joint tissue. ► Nasal instillation of our Syk siRNA inhibits recruitment of inflammatory cells to BAL fluid of allergen-sensitized mice. New approaches for the treatment of inflammatory disorders such as rheumatic arthritis (RA) and inflammatory lung disease (asthma) are needed because a significant population of patients do not experience sustained relief with currently available therapies. The tyrosine kinase Syk plays a crucial role in inflammatory signaling pathways and has gained much attention as a potential target for treatment of inflammatory disorders. We have shown that our Syk siRNA injected directly into limb joints of arthritic mice, diminishes joint swelling and reduces levels of Syk kinase and inflammatory cytokines in joint tissue. Further, our Syk siRNA, administered via nasal instillation, inhibits recruitment of inflammatory cells to the bronchoalveolar fluid of allergen-sensitized mice. We propose that targeting Syk via localized application of Syk siRNA provides an opportunity for specific knockdown of Syk kinase with minimal potential for systemic effects.