Blockade of JAK1/3 signaling with a selective inhibitor, R256, attenuates Th2 differentiation and development of allergen-induced airway hyperresponsiveness (AHR) and airway inflammation (P6047)

Abstract

Abstract JAK are major downstream regulators of signaling through cytokine receptors, activating STAT. Effective targeting of the Th2-associated JAK-STAT pathway would represent a new therapeutic approach for the treatment of asthma. Here, we studied the effects of a novel selective JAK1/3 inhibitor, R256, on Th1, Th2, and Th17 differentiation in vitro and on the development of ovalubmin-induced AHR and airway inflammation in vivo in mice. R256 prevented only Th2 differentiation in vitro and was associated with the downregulation of STAT5 and STAT6 phosphorylation. In contrast, Th2 cells were unaffected by the inhibitor when added after polarization was complete. In vivo, R256 administered during the allergen sensitization phase prevented the development of AHR, airway eosinophilia, mucus hypersecretion, and Th2 cytokine production without altering Th1 and Th17 cytokine production, indicating that selective blockade of Th2 differentiation was critical. Inhibitor administration after allergen sensitization but during the challenge phase also suppressed AHR, airway eosinophilia, and mucus hypersecretion but no effect on Th2 cytokine levels in BAL could be detected, suggesting effects on downstream cytokine receptor signaling pathways. Thus, R256-mediated inhibition of JAK1/3 activation was effective when administered both prior to and after Th2 polarization to attenuate allergen-induced Th2 dominant airway inflammation and AHR.