期刊
BIOCHEMICAL PHARMACOLOGY
卷 192, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114690
关键词
JAK inhibitor; Allergy; Eosinophils; House dust mite-induced airway inflammation
资金
- Austrian science fund [FWF W1241, DOC 31-B26]
- Pfizer
- BioTechMed Graz
Baricitinib, a JAK1/2 inhibitor, was found to be more potent in suppressing eosinophil effector function compared to the JAK3 inhibitor tofacitinib.
Background: Eosinophilic asthma is increasingly recognized as one of the most severe and difficult-to-treat asthma subtypes. The JAK/STAT pathway is the principal signaling mechanism for a variety of cytokines and growth factors involved in asthma. However, the direct effect of JAK inhibitors on eosinophil effector function has not been addressed thus far. Objective: Here we compared the effects of the JAK1/2 inhibitor baricitinib and the JAK3 inhibitor tofacitinib on eosinophil effector function in vitro and in vivo. Methods: Differentiation of murine bone marrow-derived eosinophils. Migratory responsiveness, respiratory burst, phagocytosis and apoptosis of human peripheral blood eosinophils were assessed in vitro. In vivo effects were investigated in a mouse model of acute house dust mite-induced airway inflammation in BALB/c mice. Results: Baricitinib more potently induced apoptosis and inhibited eosinophil chemotaxis and respiratory burst, while baricitinib and tofacitinib similarly affected eosinophil differentiation and phagocytosis. Of the JAK inhibitors, oral application of baricitinib more potently prevented lung eosinophilia in mice following allergen challenge. However, both JAK inhibitors neither affected airway resistance nor compliance. Conclusion: Our data suggest that the JAK1/2 inhibitor baricitinib is even more potent than the JAK3 inhibitor tofacitinib in suppressing eosinophil effector function. Thus, targeting the JAK1/2 pathway represents a promising therapeutic strategy for eosinophilic inflammation as observed in severe eosinophilic asthma.
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