Role of Janus‐Kinase 3 in Lung Inflammation

Objective Mucin hyper production is common in inflammatory and allergic lung disease such as bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis and cystic fibrosis. Excessive mucin production in the lung leads to obstruction of airways. Hence, it is critical to understand the mechanisms that regulate mucin production under normal physiological conditions and the reason for it's over production during inflammatory lung diseases. Janus kinase 3 (Jak3) is a member of the JAK family of intracellular non‐receptor tyrosine kinase that interacts with receptors for IL‐2, IL‐5, IL‐7, IL‐9, and IL‐15 through the common γ‐chain.2 Though previously Jak3 was thought to be expressed only in hematopoietic tissues, however recent studies have shown that Jak3 is expressed in many organ tissues including lungs of human and mice. Previously, we demonstrated that Jak3 plays an essential role in cytoskeletal remodeling, wound repair, and mucosal homeostasis in intestinal epithelial cells however the role of Jak3 in lung inflammation is not known. Materials and Methods Freshly dissected lung tissue from control and Jak3 knockout mice were immunostained for Jak3 ((Invitrogen) as well as different transcription factors like Muc1, Muc2, Hif‐1, Hif‐2 (Novus Biologicals), p(142) β‐catenin (Abcam), p(654) β‐catenin (Santa Cruz Biotechnology), STAT3, pSTAT3, p‐STAT6 (Cell Signaling Technology). Phosphorylation status of these transcription factors in both WT and Jak3 KO mice were assessed through western analysis. Level of pro inflammatory cytokines in the lung tissue as well as the serum sample was measured using Multianylate cytokine assay kit from Qiagen. Summary of Results Our results show that lung epithelial cells of mice express Jak3 and knock out of Jak3 resulted in substantial decrease in expression of mucin (Muc1 and Muc2). Absence of Jak3 decreases the expression of transcription factors HIF‐1, HIF‐2, and STAT3. Absence of Jak3 also decreased the tyrosine phosphorylation level of transcription factors such as STAT3, STAT6, and β‐catenin as well as increased expression of pro‐inflammatory cytokines such as IL‐6 and IL‐17A in the lung tissue lysate. Conclusion Our data suggest that Jak3 plays an important role in lung inflammation through regulating mucin expression. Further, we will determine how Jak3 regulates different lung epithelial functions such as epithelial barrier function, ion and fluid transport function and the underlying molecular mechanism of it. Support or Funding Information Crohn's & Colitis Foundation of America (CCFA Ref # 2188) and NIH (DK081661) to NK NIH (sub awarded) 1R43GM109528‐01 to NK and JM