Abstract
INTRODUCTION
Epithelial cells play an important role in immune response and eosinophilic airway inflammation, contributing to the pathogenesis of asthma. JAK/STAT pathway is involved in transduction of signal from cytokines' receptors and expression of downstream cytokines and chemokines. Therefore, inhibition of JAKs seems to be a promising approach for the therapy of asthma.
MATHERIALS AND METHODS
JAKs inhibitors: baricitinib, tofacitinib and gandotinib were used to study a role of JAK/STAT pathway in airway epithelium. Their activity among the JAKs kinases was assessed by ATP-based enzymatic assay. Their biological potency was evaluated in Primary Bronchial Tracheal Epithelial Cells (PBTEC) by WB and ELISA.
RESULTS
Baricitinib has a great potency to inhibit JAK1/JAK2, tofacitinib inhibits JAK2/JAK3, while gandotinib is a potent JAK2 inhibitor.
Table 1. Selectivity of JAKs inhibitor
We showed significant inhibition of STAT6 phosphorylation in cytokines' stimulated PBTEC after treatment with tofacitinib and baricitinib at concentration of 0,5μM, and gandotinib at 1μM. We showed corresponding decrease of eotaxin-3 secretion by cells treated with tofacitinib (IC50<10nM), baricitinib (10nM<IC50<100nM) and gandotinib (100nM<IC50<1000nM).
CONCLUSION
In airway epithelium model we observed distinct effect on eotaxin-3 release of JAKs inhibitors with higher activity towards JAK3 (tofacitinib) and JAK1 (baricitinib) from that of gandonitinib, the selective JAK2 inhibitor. Our results confirm that targeting JAK/STAT pathway represents a promising strategy for the therapy of asthma.
- © 2014 ERS
