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Preferential JAK‐3 Mediated MUC8 Enhancement in Airway Epithelial Cells upon Th2 Cytokine Stimulus
Author(s) -
Damera Gautam,
Xia Baoyun,
Sachdev Goverdhan P
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a671-c
Subject(s) - cytokine , chemokine , receptor , biology , interleukin , immunology , stat6 , mucus , secretion , stat , microbiology and biotechnology , mucin , chemistry , interleukin 4 , stat3 , medicine , endocrinology , immune system , signal transduction , ecology , biochemistry
Mucus hyper‐secretion is a pathological feature associated with airway diseases such as allergic asthma. Multiple lines of evidence suggest that allergen‐specific CD4+ Th2 cells, through the release of a variety of cytokines and chemokines play a critical role in initiating and sustaining this abnormality. With this background, we investigated the potential role of IL‐4 and IL‐9, two pleotropic Th2 cytokines predominant in asthmatic lungs, in modulating the expression of airway mucin gene MUC8 . Initially, the presence of IL‐4 and IL‐9 receptors on NCI‐H650 cells was established by immunohistochemical methods. Real time PCR analysis of total RNA from IL‐4 and IL‐9 treated cultures revealed a time and concentration dependant enhancement, reaching peak expression levels at 2.5 ng/ml and 10 ng/ml respectively, after 8 h of exposure. Nuclear‐run on assays revealed transcriptional regulation of MUC8 upon stimulus with either cytokines. Pre‐treatments with a JAK‐3 selective inhibitor, WHI‐P131 suppressed IL‐4 and IL‐9 modulated MUC8 ‐increase in a concentration dependant fashion. Western blotting analysis of cell lysates from cytokine treated confluent cultures revealed phosporylation of STAT‐6 transcription factor within 10 min of exposure. Our findings reveal that Th2 cytokines such as IL‐9 and IL‐4 increase MUC8 expression at the transcriptional level via a JAK3/STAT‐6 selective pathway. This study was supported in part by NIH grant, HL34012.