Inhibition of allergic airway inflammation by antisense-induced blockade of STAT6 expression.

Abstract

BACKGROUND:

The signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a pivotal role in asthma pathogenesis. Activation of STAT6 expression results in T helper cell type 2 (Th2) cell differentiation leading to Th2-mediated IgE production, development of allergic airway inflammation and hyperreactivity. Therefore, antagonizing the expression and/or the function of STAT6 could be used as a mode of therapy for allergic airway inflammation.

METHODS:

In this study, we synthesized a 20-mer phosphorothioate antisense oligonucleotide (ASODN) overlapping the translation starting site of STAT6 and constructed STAT6 antisense RNA (pANTI-STAT6), then transfected them into murine spleen lymphocytes and analyzed the effects of antagonizing STAT6 function in vitro and in a murine model of asthma.

RESULTS:

In vitro, we showed suppression of STAT6 expression and interleukin (IL)-4 production of lymphocytes by STAT6 ASODN. This effect was more prominent when cells were cultured with pANTI-STAT6. In a murine model of asthma associated with allergic pulmonary inflammation in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate (FITC)-labeled STAT6 ASODN to DNA uptake in lung cells was accompanied by a reduction of intracellular STAT6 expression. Such intrapulmonary blockade of STAT6 expression abrogated signs of lung inflammation, infiltration of eosinophils and Th2 cytokine production.

CONCLUSION:

These data suggest a critical role of STAT6 in the pathogenesis of asthma and the use of local delivery of STAT6 ASODN as a novel approach for the treatment of allergic airway inflammation such as in asthma.

• Authors: Xin-Rui Tian, Xin-Li Tian, Jian-Ping Bo, Shao-Gang Li, Zhuo-la Liu, Bo Niu
• Journal: Chinese medical journal (Chin Med J (Engl)) Vol. 124 Issue 1 Pg. 26-31 (Jan 2011) ISSN: 2542-5641 [Electronic] China
• PMID: 21362303 (Publication Type: Journal Article)

Chemical References

• Oligonucleotides, Antisense
• Phosphates
• RNA, Antisense
• STAT6 Transcription Factor
• Interleukin-4
• phosphorodithioic acid

Topics

• Animals
• Asthma (drug therapy, metabolism)
• Blotting, Western
• Cell Differentiation (drug effects)
• Cells, Cultured
• Female
• Interleukin-4 (metabolism)
• Lymphocytes (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Oligonucleotides, Antisense (chemistry, pharmacology)
• Phosphates (pharmacology)
• RNA, Antisense (chemistry, pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT6 Transcription Factor (genetics, metabolism)
• Th2 Cells (drug effects, metabolism)