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

Abstract

Background Janus kinases (JAK) are regulators of signaling through cytokine receptors. The importance of JAK1/3 signaling on Th2 differentiation and development of lung allergic responses has not been investigated. Objective To examine a selective JAK1/3 inhibitor (R256) on differentiation of Th 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 Th1, Th2, and Th17 differentiation in vitro. In vivo, the effects of inhibiting JAK1/3 signaling were examined by administering the inhibitor during the sensitization or during allergen challenge phases in the primary challenge model or just prior to 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 Th2 but not Th1 or Th17 cells, associated with downregulation of STAT6 and STAT5 phosphorylation. However, once polarized, Th2 cells were unaffected by the inhibitor. In vivo, R256 administered during the OVA sensitization phase prevented development of AHR, airway eosinophilia, mucus hypersecretion, and Th2 cytokine production without changes in Th1 and Th17 cytokine levels, indicating that selective blockade of Th2 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 Th2 cytokine production, suggesting the inhibitory effects were downstream of Th2 cytokine receptor signaling pathways. Conclusions Targeting the Th2-dependent JAK-STAT activation pathway represents a novel therapeutic approach for the treatment of asthma. Clinical Implications Targeting JAK1/3 signaling pathways provides a novel intervention for preventing allergen-induced alterations in lung function. Capsule Summary JAK1/3 signaling pathways are essential for initiation of Th2 differentiation and the development of lung allergic responses.

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…There has been concern that blocking JAK2 may have inhibitory effects on hematopoiesis, so there has been a search for more selective inhibitors. JAKs play a key role in differentiation of Th2 cells and a JAK1/3 inhibitor (R256) blocked the differentiation of Th2 cells and the phosphorylation of STAT5 and STAT6, but not of Th1 or Th17 cells in vitro (Ashino et al, 2014). In vivo R256 inhibited allergic inflammation, AHR, and mucus hypersecretion in a mouse model without any changes in Th2 cytokine concentrations.…”

Acute nitrogen dioxide (NO2) exposure enhances airway inflammation via modulating Th1/Th2 differentiation and activating JAK-STAT pathway

“…The analysis of STAT6-deficient mice has demonstrated that the vast majority of IL-4-induced responses are indeed mediated through the JAK-STAT pathway (Chitnis and Khoury, 2003;Kiu and Nicholson, 2012), and JAK/STAT pathway plays a critical role in the differentiation of Th2 cells (Ashino et al, 2014). JAKs are regulators of signaling through cytokine receptors, among which JAK1 and JAK3 play critical roles in the initiation of inflammation and have been investigated as potent therapeutic targets in a variety of inflammatory diseases.…”

“…JAKs are regulators of signaling through cytokine receptors, among which JAK1 and JAK3 play critical roles in the initiation of inflammation and have been investigated as potent therapeutic targets in a variety of inflammatory diseases. A selective JAK1/3 inhibitor inhibited differentiation of Th2 cells, down-regulated STAT6 and STAT5 phosphorylation and prevented the development of AHR, airway eosinophilia, mucus hypersecretion, and Th2 cytokine production (Ashino et al, 2014). STAT6 has been demonstrated to regulate many pathologic features of lung inflammatory responses in animal models including airway eosinophilia, epithelial mucus production, smooth muscle changes, Th2 cell differentiation, and IgE production from B cells (Walford and Doherty, 2013).…”

“…JAK-STAT pathway is the generally accepted mechanism for Th2 differentiation predominantly and Th1/Th2 differentiation imbalance (Ashino et al, 2014). To test the hypothesis, we examined the expression of STAT6 and JAK3.…”

“…Also, pro-inflammatory cytokines IL-1b, IL-6 and ICAM-1 play a critical role on the human MUC5AC promoter activity (Barnes, 2008a). Asthma is considered as a complex disease, and the generally accepted view of its mechanism is that Th2 differentiation predominantly, resulting in the imbalance in the ratio of Th1/Th2 differentiation (Zhang et al, 1999) and activating the following JAK-STAT signaling pathway (Li et al, 2005;Ashino et al, 2014;Walford and Doherty, 2013).…”