Janus kinase 1/3 signaling pathways are key initiators of TH2 differentiation and lung allergic responses

Background: Janus kinases (JAKs) are regulators of signaling through cytokine receptors. The importance of JAK1/3 signaling on T(H)2 differentiation and development of lung allergic responses has not been investigated. Objective: We sought to examine a selective JAK1/3 inhibitor (R256) on differentiation of T-H subsets in vitro and on development of ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and inflammation in an experimental model of asthma. Methods: A selective JAK1/3 inhibitor was used to assay the importance of this pathway on induction of T(H)1, T(H)2, and T(H)17 differentiation in vitro. In vivo, the effects of inhibiting JAK1/3 signaling were examined by administering the inhibitor during the sensitization or allergen challenge phases in the primary challenge model or just before provocative challenge in the secondary challenge model. Airway inflammation and AHR were examined after the last airway challenge. Results: In vitro, R256 inhibited differentiation of T(H)2 but not T(H)1 or T(H)17 cells, which was associated with downregulation of signal transducer and activator of transcription (STAT) 6 and STAT5 phosphorylation. However, once polarized, T(H)2 cells were unaffected by the inhibitor. In vivo, R256 administered during the OVA sensitization phase prevented the development of AHR, airway eosinophilia, mucus hypersecretion, and T(H)2 cytokine production without changes in T(H)1 and T(H)17 cytokine levels, indicating that selective blockade of T(H)2 differentiation was critical. Inhibitor administration after OVA sensitization but during the challenge phases in the primary or secondary challenge models similarly suppressed AHR, airway eosinophilia, and mucus hypersecretion without any reduction in T(H)2 cytokine production, suggesting the inhibitory effects were downstream of T(H)2 cytokine receptor signaling pathways. Conclusions: Targeting the T(H)2-dependent JAK/STAT activation pathway represents a novel therapeutic approach for the treatment of asthma.